8-azabicyclo[3.2.1]octane compounds as mu opioid receptor antagonists

ABSTRACT

The invention provides novel 8-azabicyclo[3.2.1]octane compounds of formula (I): 
                         
wherein R 1 , R 2 , R 3 , A, and G are defined in the specification, or a pharmaceutically-acceptable salt or solvate thereof, that are antagonists at the mu opioid receptor. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat conditions associated with mu opioid receptor activity, and processes and intermediates useful for preparing such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. Ser. No.14/534,798, filed Nov. 6, 2014, which is a continuation of U.S. Ser. No.14/156,014, filed Jan. 15, 2014, now U.S. Pat. No. 8,927,573, which is adivisional application of U.S. Ser. No. 13/527,942, filed Jun. 20, 2012,now U.S. Pat. No. 8,664,242, which is a continuation application of U.S.Ser. No. 12/578,715, filed Oct. 14, 2009, now U.S. Pat. No. 8,263,618 B2which is a divisional application of U.S. Ser. No. 11/711,961, filedFeb. 28, 2007, now U.S. Pat. No. 7,622,508 B2, which claims the benefitof U.S. Provisional Application No. 60/777,962, filed on Mar. 1, 2006,and 60/841,028, filed on Aug. 30, 2006, the disclosures of which areincorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

Field of the Invention

The invention is directed to 8-azabicyclo[3.2.1]octane compounds whichare useful as mu opioid receptor antagonists. The invention is alsodirected to pharmaceutical compositions comprising such compounds,methods of using such compounds for treating or ameliorating medicalconditions mediated by mu opioid receptor activity, and processes andintermediates useful for preparing such compounds.

State of the Art

It is now generally understood that endogenous opioids play a complexrole in gastrointestinal physiology. Opioid receptors are expressedthroughout the body, both in the central nervous system and inperipheral regions including the gastrointestinal (GI) tract.

Compounds which function as agonists at opioid receptors, of whichmorphine is a prototypical example, are the mainstays of analgesictherapy for the treatment of moderate to severe pain. Unfortunately, useof opioid analgesics is often associated with adverse effects on the GItract, collectively termed opioid-induced bowel dysfunction (OBD). OBDincludes symptoms such as constipation, decreased gastric emptying,abdominal pain and discomfort, bloating, nausea, and gastroesophagealreflux. Both central and peripheral opioid receptors are likely involvedin the slowdown of gastrointestinal transit after opioid use. However,evidence suggests that peripheral opioid receptors in the GI tract areprimarily responsible for the adverse effects of opioids on GI function.

Since the side effects of opioids are predominantly mediated byperipheral receptors, whereas the analgesia is central in origin, aperipherally selective antagonist can potentially block undesirableGI-related side effects without interfering with the beneficial centraleffects of analgesia or precipitating central nervous system withdrawalsymptoms.

Of the three major opioid receptor subtypes, denoted mu, delta, andkappa, most clinically-used opioid analgesics are thought to act via muopioid receptor activation to exert analgesia and to alter GI motility.Accordingly, peripherally selective mu opioid antagonists are expectedto be useful for treating opioid-induced bowel dysfunction. Preferredagents will demonstrate significant binding to mu opioid receptors invitro and be active in vivo in GI animal models.

Postoperative ileus (POI) is a disorder of reduced motility of the GItract that occurs after abdominal or other surgery. The symptoms of POIare similar to those of OBD. Furthermore, since surgical patients areoften treated during and after surgery with opioid analgesics, theduration of POI may be compounded by the reduced GI motility associatedwith opioid use. Mu opioid antagonists useful for treating OBD aretherefore also expected to be beneficial in the treatment of POI.

SUMMARY OF THE INVENTION

The invention provides novel compounds that possess mu opioid receptorantagonist activity.

Accordingly, the invention provides a compound of formula (I):

wherein:

R¹ is selected from —OR^(a), —C(O)NR^(a)R^(b); —NHS(O)₂R^(c),—NR^(a)R^(b), —C(O)OR^(a), and —CH₂OH;

A is C₁₋₄alkylenyl;

R² is C₃₋₁₂cycloalkyl or C₆₋₁₀aryl, wherein C₃₋₁₂cycloalkyl andC₆₋₁₀aryl are each optionally substituted with one —OR^(a), with one ortwo halo, with one or two C₁₋₃alkyl substituted with two or three halo;or with one, two, three or four C₁₋₃alkyl;

G is C₁₋₄alkylenyl;

R³ is selected from hydrogen, —C(O)R⁴, —C(O)NHR⁵, —S(O)₂R^(c), and—S(O)₂NR^(a)R^(b);

R⁴ is C₃₋₆cycloalkyl or C₁₋₆alkyl,

wherein

-   -   C₃₋₆cycloalkyl is optionally substituted with one —OR^(a), and    -   C₁₋₆alkyl is optionally substituted with one or two substituents        selected from —OR^(a), —C(O)OR^(a), —S(O)₂R⁶, —C(O)NR^(a)R^(b),        —NR^(a)R^(b), —NHC(O)NR^(a)R^(b), —CN, C₃₋₆ cycloalkyl, and        phenyl; or with one -D-(CH₂)_(j)—R⁷,

wherein D is

-   -   j is 1, 2, or 3, n is 1 or 2, and p is 1 or 2,    -   R⁶ is C₁₋₃alkyl optionally substituted with R⁷    -   R⁷ is —C(O)OR^(a), —C(O)NR^(a)R^(b), —NR^(a)R^(b), or        —NHC(O)NR^(a)R^(b)

R⁵ is C₁₋₆alkyl, benzo[1.3]dioxol, or —(CH₂)_(q)-phenyl,

-   -   wherein phenyl is optionally substituted with one or two        substituents selected from halo, —OR^(a), C₁₋₃alkyl, and        C₁₋₃alkoxy, wherein C₁₋₃alkyl, and C₁₋₃alkoxy are optionally        substituted with 2 or 3 halo, and    -   q is 0, 1, or 2;

R^(a) and R^(b) are each independently hydrogen or C₁₋₄alkyl, and;

R^(c) is C₁₋₃alkyl;

provided that when R² is phenyl substituted at the 4 position, R³ is not—C(O)R⁴ wherein R⁴ is C₁₋₄alkyl substituted with —C(O)OR^(a);

or a pharmaceutically-acceptable salt or solvate thereof.

The invention also provides a pharmaceutical composition comprising acompound of the invention and a pharmaceutically-acceptable carrier.

The invention also provides a method of treating a disease or conditionassociated with mu opioid receptor activity, e.g. a disorder of reducedmotility of the gastrointestinal tract such as opioid-induced boweldysfunction and post-operative ileus, the method comprisingadministering to the mammal, a therapeutically effective amount of acompound or of a pharmaceutical composition of the invention.

The compounds of the invention can also be used as research tools, i.e.to study biological systems or samples, or for studying the activity ofother chemical compounds. Accordingly, in another of its method aspects,the invention provides a method of using a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as a research toolfor studying a biological system or sample or for discovering newcompounds having mu opioid receptor activity, the method comprisingcontacting a biological system or sample with a compound of theinvention and determining the effects caused by the compound on thebiological system or sample.

In separate and distinct aspects, the invention also provides syntheticprocesses and intermediates described herein, which are useful forpreparing compounds of the invention.

The invention also provides a compound of the invention as describedherein for use in medical therapy, as well as the use of a compound ofthe invention in the manufacture of a formulation or medicament fortreating a disease or condition associated with mu opioid receptoractivity, e.g. a disorder of reduced motility of the gastrointestinaltract, in a mammal.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows an x-ray powder diffraction pattern of crystalline3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamideglycolate of the invention.

FIG. 2 shows an x-ray powder diffraction pattern of crystalline3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamideoxalate of the invention.

FIG. 3 shows an x-ray powder diffraction pattern of crystalline3-endo-(8-{2-[(4,4-difluorocyclohexylmethyl)-(2-hydroxyacetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamidephosphate of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides 8-azabicyclo[3.2.1]octane mu opioid receptorantagonists of formula (I), or pharmaceutically-acceptable salts orsolvates thereof. The following substituents and values are intended toprovide representative examples of various aspects of this invention.These representative values are intended to further define such aspectsand are not intended to exclude other values or limit the scope of theinvention.

In a specific aspect of the invention, R¹ is selected from —OR^(a),—C(O)NR^(a)R^(b); —NHS(O)₂R^(c), —NR^(a)R^(b), —C(O)OR^(a), and —CH₂OH.

In other specific aspects, R¹ is selected from —OR^(a),—C(O)NR^(a)R^(b); and —NHS(O)₂R^(c), or R¹ is —OR^(a) or—C(O)NR^(a)R^(b), or R¹ is —OH or —C(O)NR^(a)R^(b).

In yet another specific aspect, R¹ is —OH or —C(O)NH₂.

In a further specific aspect, R¹ is —C(O)NH₂.

In a specific aspect, A is C₁₋₄alkylenyl.

In other specific aspects, A is —(CH₂)₂—, —CH(CH₃)—, or —CH₂—; or A is—(CH₂)₂— or —CH₂—; or A is —CH₂—.

In a specific aspect, G is C₁₋₄alkylenyl.

In other specific aspects, G is —(CH₂)₃—, —(CH₂)₂—, or —CH₂—; or G is—(CH₂)₂— or —CH₂—; or G is —CH₂—.

In a specific aspect, R² is C₃₋₁₂cycloalkyl or C₆₋₁₀aryl, whereinC₃₋₁₂cycloalkyl and C₆₋₁₀aryl are each optionally substituted with one—OR^(a), with one or two halo, with one or two C₁₋₃alkyl substitutedwith two or three halo; or with one, two, three or four C₁₋₃alkyl.

In another specific aspect, R² is C₃₋₁₂cycloalkyl or C₆₋₁₀aryl, whereinC₃₋₁₂cycloalkyl and C₆₋₁₀aryl are each optionally substituted with one—OR^(a), with one or two halo, or with one or two C₁₋₃alkyl optionallysubstituted with two or three halo.

In another specific aspect, R² is C₃₋₁₂cycloalkyl or C₆₋₁₀aryl, whereinC₃₋₁₂cycloalkyl and C₆₋₁₀aryl are each optionally substituted with oneor two halo, or with one or two C₁₋₃alkyl optionally substituted with 2or 3 halo. Representative R² groups within this aspect include, but arenot limited to, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, phenyl,and naphthyl, wherein cyclohexyl, phenyl, and naphthyl are eachoptionally substituted with one or two halo or with C₁₋₃alkylsubstituted with two or three halo.

In another specific aspect, R² is cyclobutyl, cyclopentyl, cyclohexyl,adamantyl, or phenyl, wherein cyclohexyl and phenyl are each optionallysubstituted with one or two halo or with C₁₋₃alkyl substituted with twoor three halo.

In another specific aspect, R² is cyclohexyl or phenyl, whereincyclohexyl and phenyl are each optionally substituted with one or twohalo or with C₁₋₃alkyl substituted with two or three halo; or R² iscyclohexyl or phenyl, wherein cyclohexyl and phenyl are each optionallysubstituted with one or two halo.

In another specific aspect, R² is cyclohexyl optionally substituted withone or two halo.

In still another specific aspect, R² is cyclohexyl.

In yet another specific aspect, R² is phenyl optionally substituted withone or two halo.

In yet another specific aspect, R² is phenyl.

In a specific aspect, R³ is selected from hydrogen, —C(O)R⁴, —C(O)NHR⁵,—S(O)₂R^(c), and —S(O)₂NR^(a)R^(b).

In another specific aspect, R³ is selected from hydrogen, —C(O)R⁴,—S(O)₂R^(c), and —S(O)₂NR^(a)R^(b)

In a specific aspect, R³ is selected from hydrogen, —C(O)R⁴, and—C(O)NHR⁵.

In other specific aspects, R³ is —C(O)R⁴ or —C(O)NHR⁵, or R³ is —C(O)R⁴.

In another specific aspect, R³ is —C(O)R⁴ wherein R⁴ is C₃₋₆cycloalkylor C₁₋₆alkyl, and wherein C₁₋₆alkyl is optionally substituted with oneor two —OR^(a), or with one substituent selected from —C(O)OR^(a),—S(O)₂R⁶, —C(O)NR^(a)R^(b), —NR^(a)R^(b), and C₃₋₆cycloalkyl, and R⁶ isC₁₋₃alkyl optionally substituted with R⁷, wherein R⁷ is —C(O)OR^(a).

In another specific aspect, R³ is —C(O)R⁴ wherein R⁴ is C₃₋₆cycloalkylor C₁₋₆alkyl, wherein C₃₋₆cycloalkyl is optionally substituted with one—OR^(a), and C₁₋₆alkyl is optionally substituted with one or twosubstituents selected from —OR^(a), —C(O)OR^(a), —S(O)₂R⁶,—C(O)NR^(a)R^(b), —NR^(a)R^(b), —CN, C₃₋₆cycloalkyl, and phenyl, whereinR⁶ is C₁₋₃alkyl optionally substituted with R⁷, wherein R⁷ is—C(O)OR^(a).

In another specific aspect, R³ is —C(O)R⁴ wherein R⁴ is C₅-6 cycloalkyloptionally substituted with one —OH.

In other specific aspects R³ is —C(O)R⁴, wherein R⁴ is C₁₋₄alkyl whereinC₁₋₄alkyl is optionally substituted with one or two substituentsselected from —OR^(a), —S(O)₂R⁶, —NR^(a)R^(b), —CN, C₃₋₆cycloalkyl, andphenyl, wherein R⁶ is C₁₋₃alkyl; or R⁴ is C₁₋₄alkyl wherein C₁₋₄alkyl isoptionally substituted with one or two substituents selected from —OH,—OCH₃, —S(O)₂CH₃, —NH₂, —NHCH₃, —NH(CH₃)₂, and phenyl. Representativevalues of R⁴ within this aspect include but are not limited to —CH₂OH,—CH(OH)CH₂OH, —CH₂SO₂CH₃, —CH₂SO₂CH₂C(O)OH, —CH₂CN, —CH₂OCH₃,—C(CH₃)₂OH, —CH(CH₃)OH, —CH(OH)CH(CH₃) OH, —CH(OH)CH₃, —(CH₂)N(CH₃)₂,and CH(NHCH₃)CH₂OH.

In still another specific aspect, R³ is —C(O)R⁴ wherein R⁴ is selectedfrom —CH₂OH, —CH(OH)CH₂OH, —CH(OH)CH₃, and —CH₂SO₂CH₃.

In another specific aspect, R³ is —C(O)NHR⁵.

In another specific aspect R³ is —C(O)NHR⁵, wherein R⁵ is C₁₋₆alkyl,benzo[1.3]dioxol, or —(CH₂)_(q)-phenyl, wherein q is 0 or 1 and phenylis optionally substituted with one or two substituents selected fromchloro, fluoro, —OH, and —OCF₂.

In other specific aspects, R³ is —C(O)NHR⁵, wherein R⁵ is C₁₋₆alkyl orbenzo[1.3]dioxol; or R⁵ is —CH(CH₃)₂ or benzo[1.3]dioxol; or R⁵ is—CH(CH₃)₂.

The invention further provides a compound of formula (I) wherein:

R¹ is —OR^(a) or —C(O)NR^(a)R^(b);

A is —(CH₂)₂—, or —CH₂—;

G is —(CH₂)₂— or —CH₂—;

R² is selected from cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, andphenyl, wherein cyclohexyl and phenyl are each optionally substitutedwith 1 or 2 halo or with C₁₋₃alkyl substituted with 2 or 3 halo;

R³ is selected from —C(O)R⁴, —S(O)₂R^(c), —S(O)₂NR^(a)R^(b), and—C(O)NHR⁵;

R⁴ is C₃₋₆cycloalkyl or C₁₋₆alkyl, wherein C₃₋₆cycloalkyl is optionallysubstituted with one —OR^(a), and C₁₋₆alkyl is optionally substitutedwith one or two substituents selected from —OR^(a), —C(O)OR^(a),—S(O)₂R⁶, —C(O)NR^(a)R^(b), —NR^(a)R^(b), —CN, C₃₋₆cycloalkyl, andphenyl, wherein R⁶ is C₁₋₃alkyl optionally substituted with R⁷, whereinR⁷ is —C(O)OR^(a);

R⁵ is C₁₋₄alkyl, benzo[1.3]dioxol, or —(CH₂)_(q)-phenyl, wherein q is 0or 1 and phenyl is optionally substituted with one or two substituentsselected from chloro, fluoro, —OH, and —OCF₂;

R^(a) and R^(b) are each independently hydrogen or C₁₋₃alkyl; and

R^(c) is C₁₋₃alkyl;

provided that when R² is phenyl substituted at the 4 position, R³ is not—C(O)R⁴ wherein R⁴ is C₁₋₄alkyl substituted with —C(O)OH;

or a pharmaceutically-acceptable salt or solvate thereof.

In yet another aspect, the invention provides a compound of formula (I)wherein:

R¹ is —OH or —C(O)NH₂;

A is —(CH₂)₂— or —CH₂—;

G is —(CH₂)₂— or —CH₂—;

R² is cyclohexyl or phenyl, wherein cyclohexyl is optionally substitutedwith 1 or 2 halo;

R³ is —C(O)R⁴ or —C(O)NHR⁵;

R⁴ is selected from —CH₂OH, —CH(OH)CH₂OH, —CH(OH)CH₃, and —CH₂SO₂CH₃;and

R⁵ is —CH(CH₃)₂ or benzo[1.3]dioxol;

or a pharmaceutically-acceptable salt or solvate thereof.

The invention further provides a compound of formula (I′):

wherein:

R² is cyclohexyl or phenyl, wherein cyclohexyl and phenyl are eachoptionally substituted with one or two halo; and

R⁴ is C₃₋₆cycloalkyl or C₁₋₄alkyl,

wherein

-   -   C₃₋₆cycloalkyl is optionally substituted with one —OR^(a), and    -   C₁₋₄alkyl is optionally substituted with one or two substituents        selected from —OR^(a), —S(O)₂R⁶, —NR^(a)R^(b), —CN, and        C₃₋₆cycloalkyl,    -   R^(a) and R^(b) are each independently hydrogen or C₁₋₃alkyl;        and    -   R⁶ is C₁₋₃alkyl;

or a pharmaceutically-acceptable salt or solvate thereof.

Within this aspect, the invention provides a compound of formula (I′)wherein R⁴ is C₁₋₄alkyl optionally substituted with one or twosubstituents selected from —OH, —OCH₃, —S(O)₂CH₃, —NH₂, —NHCH₃, and—NH(CH₃)₂.

Further within this aspect, the invention provides a compound of formula(I′) wherein R² is cyclohexyl or 4,4-difluorocyclohexyl, and R⁴ isC₁₋₄alkyl substituted with one or two —OH.

The invention further provides the compounds of Examples 1-204 herein.

The chemical naming convention used herein is illustrated for thecompound of Example 1:

which isN-benzyl-2-hydroxy-N-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}acetamide.Alternatively, using the IUPAC conventions as implemented in AutoNomsoftware, (MDL Information Systems, GmbH, Frankfurt, Germany), thecompound is denotedN-Benzyl-2-hydroxy-N-{2-[(1R,3R,5S)-3-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}acetamide.The names used herein therefore correspond to the IUPAC notation withthe endo orientation of the substituted phenyl group with respect to the8-azabicyclo[3.2.1]octane group indicated explicitly. All of thecompounds of the invention are in the endo orientation. For convenience,as used herein, the term “8-azabicyclooctane” means8-azabicyclo[3.2.1]octane.

In addition to the endo stereochemistry with respect to the bicyclogroup, the compounds of the invention may contain a chiral center in thesubstituents R⁴, R⁵, or A. Accordingly, the invention includes racemicmixtures, pure stereoisomers, and stereoisomer-enriched mixtures of suchisomers, unless otherwise indicated. When the stereochemistry of acompound is specified, including both the orientation with respect tothe 8-azabicyclooctane group and the chirality in any substituents R⁴,R⁵, or A, it will be understood by those skilled in the art, that minoramounts of other stereoisomers may be present in the compositions of theinvention unless otherwise indicated, provided that any utility of thecomposition as a whole is not eliminated by the presence of such otherisomers.

DEFINITIONS

When describing the compounds, compositions and methods of theinvention, the following terms have the following meanings, unlessotherwise indicated.

The term “alkyl” means a monovalent saturated hydrocarbon group whichmay be linear or branched or combinations thereof. Unless otherwisedefined, such alkyl groups typically contain from 1 to 10 carbon atoms.Representative alkyl groups include, by way of example, methyl, ethyl,n-propyl (n-Pr), isopropyl (i-Pr), n-butyl (n-Bu), sec-butyl, isobutyl,tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl andthe like.

The term “alkylenyl” means a divalent saturated hydrocarbon group whichmay be linear or branched or combinations thereof. Unless otherwisedefined, such alkylenyl groups typically contain from 1 to 10 carbonatoms. Representative alkylenyl groups include, by way of example,methylene, ethylene, n-propylene, n-butylene, propane-1,2-diyl(1-methylethylene), 2-methylpropane-1,2-diyl (1,1-dimethylethylene) andthe like.

The term “alkoxy” means a monovalent group —O-alkyl, where alkyl isdefined as above. Representative alkoxy groups include, by way ofexample, methoxy, ethoxy, propoxy, butoxy, and the like.

The term “cycloalkyl” means a monovalent saturated carbocyclic groupwhich may be monocyclic or multicyclic. Unless otherwise defined, suchcycloalkyl groups typically contain from 3 to 10 carbon atoms.Representative cycloalkyl groups include, by way of example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, adamantyl, and the like.

The term “aryl” means a monovalent aromatic hydrocarbon having a singlering (i.e. phenyl) or fused rings (i.e. napthalene). Unless otherwisedefined, such aryl groups typically contain from 6 to 10 carbon ringatoms. Representative aryl groups include, by way of example, phenyl,and napthalene-1-yl, napthalene-2-yl and the like.

The term “halo” means fluoro, chloro, bromo or iodo.

The term “compound” means a compound that was synthetically prepared orprepared in any other way, such as by metabolism.

The term “therapeutically effective amount” means an amount sufficientto effect treatment when administered to a patient in need of treatment.

The term “treatment” as used herein means the treatment of a disease,disorder, or medical condition in a patient, such as a mammal(particularly a human) which includes:

-   -   (a) preventing the disease, disorder, or medical condition from        occurring, i.e., prophylactic treatment of a patient;    -   (b) ameliorating the disease, disorder, or medical condition,        i.e., eliminating or causing regression of the disease,        disorder, or medical condition in a patient, including        counteracting the effects of other therapeutic agents;    -   (c) suppressing the disease, disorder, or medical condition,        i.e., slowing or arresting the development of the disease,        disorder, or medical condition in a patient; or    -   (d) alleviating the symptoms of the disease, disorder, or        medical condition in a patient.

The term “pharmaceutically-acceptable salt” means a salt prepared froman acid or base which is acceptable for administration to a patient,such as a mammal. Such salts can be derived frompharmaceutically-acceptable inorganic or organic acids and frompharmaceutically-acceptable bases. Typically,pharmaceutically-acceptable salts of compounds of the present inventionare prepared from acids.

Salts derived from pharmaceutically-acceptable acids include, but arenot limited to, acetic, adipic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic,glycolic, hydrobromic, hydrochloric, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, oxalic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic, xinafoic(1-hydroxy-2-naphthoic acid), naphthalene-1,5-disulfonic acid and thelike.

The term “solvate” means a complex or aggregate formed by one or moremolecules of a solute, i.e. a compound of the invention or apharmaceutically-acceptable salt thereof, and one or more molecules of asolvent. Such solvates are typically crystalline solids having asubstantially fixed molar ratio of solute and solvent. Representativesolvents include by way of example, water, methanol, ethanol,isopropanol, acetic acid, and the like. When the solvent is water, thesolvate formed is a hydrate.

It will be appreciated that the term “or a pharmaceutically-acceptablesalt or solvate thereof” is intended to include all permutations ofsalts and solvates, such as a solvate of a pharmaceutically-acceptablesalt of a compound of formula (I).

The term “amino-protecting group” means a protecting group suitable forpreventing undesired reactions at an amino nitrogen. Representativeamino-protecting groups include, but are not limited to, formyl; acylgroups, for example alkanoyl groups, such as acetyl andtri-fluoroacetyl; alkoxycarbonyl groups, such as tert-butoxycarbonyl(Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl(Bn), trityl (Tr), and 1,1-di-(4′-methoxyphenyl)methyl; silyl groups,such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS); andthe like.

General Synthetic Procedures

Compounds of the invention can be prepared from readily availablestarting materials using the following general methods and procedures.Although a particular aspect of the present invention is illustrated inthe schemes below, those skilled in the art will recognize that allaspects of the present invention can be prepared using the methodsdescribed herein or by using other methods, reagents and startingmaterials known to those skilled in the art. It will also be appreciatedthat where typical or preferred process conditions (i.e., reactiontemperatures, times, mole ratios of reactants, solvents, pressures,etc.) are given, other process conditions can also be used unlessotherwise stated. Optimum reaction conditions may vary with theparticular reactants or solvent used, but such conditions can bedetermined by one skilled in the art by routine optimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group, as well assuitable conditions for protection and deprotection, are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and G. M. Wuts, ProtectingGroups in Organic Synthesis, Third Edition, Wiley, New York, 1999, andreferences cited therein.

In one method of synthesis, compounds of the invention are prepared asillustrated in Scheme A. (The substituents and variables shown in thefollowing schemes have the definitions provided above unless otherwiseindicated).

In Scheme A, R^(4a) represents R⁴ or a protected form of R⁴, and Lrepresents a leaving group, such as chloro or bromo, or R^(4a)C(O)-Lrepresents a carboxylic acid or a carboxylate salt. For example, toprepare a compound in which R⁴ is —CH₂OH, a useful reagent is acetoxyacetyl chloride, in which R^(4a) is —CH₂OC(O)CH₃ and L is chloro. WhenR^(4a) is a protected form of R⁴, reaction (i) also includes adeprotection step, which is not shown. To prepare a compound in which R¹represents amino, preferably, a protected amino group is used for R¹ inintermediate (II) and the reaction sequence includes a finaldeprotection step.

Optimal reaction conditions for reaction (i) of Scheme A to preparecompounds of formula (Ia) may vary depending on the chemical propertiesof the reagent R^(4a)C(O)-L, as is well known to those skilled in theart. For example, when L is a halo leaving group, such as chloro,reaction (i) is typically conducted by contacting intermediate (II) withbetween about 1 and about 2 equivalents of a compound of formulaR^(4a)C(O)-L in an inert diluent, such as dichloromethane, in thepresence of an excess of base, for example between about 3 and about 6equivalents of base, such as N,N-diisopropylethylamine or triethylamine.Suitable inert diluents also include 1,1,2,2-tetrachloroethane,tetrahydrofuran, dimethylacetamide, and the like. The reaction istypically conducted at a temperature in the range of about −50° C. toabout 30° C. for about a quarter hour to about 16 hours, or until thereaction is substantially complete.

When the reagent R^(4a)C(O)-L is a carboxylic acid or a carboxylatesalt, reaction (i) is typically conducted by contacting intermediate(II) with between about 1 and about 5 equivalents of the acidR^(4a)C(O)OH or the carboxylate salt, for example, R^(4a)C(O)OLi, in aninert diluent, in the presence of an excess of base, both as describedabove, and in the presence of between about 1 and about 6 equivalents ofan activating agent such as N,N-carbonyl diimidazole (CDI),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (HATU) or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC). The reaction istypically conducted at a temperature in the range of about 25° C. toabout 100° C. for about 2 hours to about 16 hours, or until the reactionis substantially complete.

As described in the examples below, particular compounds of formula (Ia)may be prepared by coupling an intermediate of formula (II) withalternative reagents, such as cyclic anhydrides or a dioxolanecarboxylic acid.

The preparation of urea compounds of formula (Ib) is illustrated inreaction (ii) of Scheme A. The reaction is typically conducted bycontacting intermediate (II) with between about 1 and about 2equivalents of an isocyanate compound R⁵—N═C═O in the presence ofbetween about 3 and about 6 equivalents of base, such asN,N-diisopropylethylamine. The reaction is typically conducted atambient temperature for about an hour to about 16 hours, or until thereaction is substantially complete.

One general procedure for the preparation of an intermediate of formula(II) is illustrated in Scheme B1, where P¹ represents anamino-protecting group.

An intermediate of formula (III), referred to here as a “phenyltropane”,is reductively N-alkylated by reaction with an aldehyde of formula (IV)to provide a protected intermediate (V) which is deprotected byconventional procedures to provide intermediate (II).

The initial reaction is typically conducted by contacting intermediate(III) with between about 1 and about 2 equivalents of an aldehyde offormula (IV) in a suitable diluent, typically an inert diluent, in thepresence of between about 0.9 and about 2 equivalents of a reducingagent. The reaction is typically conducted at a temperature in the rangeof about 0° C. to ambient temperature for about a half hour to about 3hours or until the reaction is substantially complete. Suitable inertdiluents include dichloromethane and the like listed above.Additionally, alcohols, such as methanol or ethanol, may be used as thediluent. Typical reducing agents include sodium triacetoxyborohydride,sodium borohydride, and sodium cyanoborohydride. The product (V) isisolated by conventional means. The deprotection of (V) uses standardprocedures. For example, when the protecting group P¹ is Boc, (V) istypically treated with an acid, such as trifluoroacetic acid to provideintermediate (II). In the reaction of Scheme B1, intermediate (III) maybe provided in free base or in salt form. In the latter case, about 1equivalent of base may optionally be used in the reaction.

Another general procedure for the preparation of an intermediate offormula (II) is illustrated in Scheme B2.

where L′ represents a sulfonate leaving group such as mesylate ortosylate. The reaction is typically conducted by contacting intermediate(IIa) with between about 1 and about 2 equivalents of amine R²-G-NH₂ inan inert diluent, such as dimethylformamide or an alcohol, in thepresence of between about 1 and 2 equivalents of base, such asN,N-diisopropylethylamine, or the like. The reaction is typicallyconducted at a temperature in the range of about 25° C. to about 80° C.for about a half hour to about 2 hours or until the reaction issubstantially complete.

Intermediates of formula (IIa) can be prepared by standard processes.For example, an intermediate of formula (IIa) in which L′ is mesylatecan be prepared as described in Example 130. A halo substituted alcoholof the form HO-A-CH₂—X, where X is a halo is reacted with phenyltropane(III) to provide an alcohol intermediate in which HO-A-CH₂— is coupledto the tropane nitrogen, which is then reacted with methane sulfonylchloride to provide intermediate (IIa).

A third process for the preparation of intermediate (II) is illustratedin Scheme B3

where G^(a) is defined such that G^(a)-CH₂ is the variable G, i.e. G^(a)is C₁₋₃alkylenyl or G^(a) is a covalent bond. Intermediate (IIb) isreductively N-alkylated by reaction with the aldehyde R²-G^(a)-C(O)H toprovide intermediate (II). The reaction is typically conducted under theconditions described above for the N-alkylation reaction of (III) inScheme B1. Intermediate (IIb) may be prepared by reductive N-alkylationof phenyltropane (III) by a protected amino aldehyde of the formN(HP¹)-A-C(O)H, followed by a deprotection step.

In another alternative process for the preparation of intermediate (II)a carboxylic acid reagent is coupled with the phenyltropane (III) in thepresence of an amide coupling agent to form an amide intermediate whichis then reduced to provide intermediate (II), as described, for example,in Preparation 22 below.

In yet another alternative process, an intermediate of formula (II) inwhich the variable A is methylene, is prepared by the process of SchemeC.

As shown in Scheme C, intermediate (III) is reductively N-alkylated byreaction with dimethoxyacetaldehyde to provide the acetal intermediate(VI) under N-alkylation conditions described previously. Next, theacetal intermediate (VI) is hydrolyzed in an aqueous solution of astrong acid, for example 3N or 6N HCl to provide the aldehydeintermediate (VII) as a hydrochloride salt. This reaction is typicallyconducted at a temperature of between about 20 and about 40° C. forabout 3 to about 72 hours or until the reaction is substantiallycomplete.

Finally, reductive amination of intermediate (VII) with an amine of theformula R²-G-NH₂ provides the intermediate of formula (II′). Typically,aldehyde (VII) in an inert diluent is contacted with between about 1 andabout 2 equivalents of the amine in the presence of between about 1 andabout 2 equivalents of a reducing agent and about one equivalent ofbase. The reaction is typically conducted at ambient temperature forbetween about 15 minutes and 2 hours or until the reaction issubstantially complete.

Intermediates (III) and (IV) can be prepared from readily availablestarting materials. For example, one process for the preparation of thephenyltropane (III′) in which R¹ is hydroxy is illustrated in Scheme D.

where Bn denotes the amino-protecting group benzyl. Protected tropanone(VIII) can be prepared by the reaction of 2,5-dimethoxy tetrahydrofuranwith benzylamine and 1,3-acetonedicarboxylic acid in an acidic aqueoussolution in the presence of a buffering agent as described in US2005/0228014. (See also, U.S. Pat. No. 5,753,673).

First, tropanone (VIII) is added to a solution of between about 1 andabout 2 equivalents of the Grignard reagent 3-methoxyphenyl magnesiumbromide in an inert diluent. The reaction is typically conducted at atemperature of between about 0° C. and about 10° C. for between about 1and about 3 hours or until the reaction is substantially complete.Transmetalation of the Grignard reagent from magnesium to cerium byreaction with an equivalent amount of cerous chloride prior to use isadvantageous for obtaining a good yield of intermediate (IX). Thehydroxy substituent is eliminated from intermediate (IX) by treatmentwith aqueous 6N HCl to provide the hydrochloride salt of intermediate(X). This reaction is typically conducted at a temperature of betweenabout 50° C. and about 100° C. for between about 1 and about 3 hours oruntil the reaction is substantially complete.

Hydrogenation of intermediate (X) saturates the double bond of thealkene moiety and removes the benzyl protecting group to provideintermediate (XI). Typically, the reaction is conducted by exposing theHCl salt of (X) dissolved in ethanol to a hydrogen atmosphere in thepresence of a transition metal catalyst. Finally, the methyl group isremoved from intermediate (XI) by contacting a cooled solution ofintermediate (XI) in an inert diluent with between about 1 and about 2equivalents of boron tribromide, hydrogen bromide, or boron trichloride.The reaction is typically conducted at a temperature of between about−80° C. and about 0° C. for between about 12 and about 36 hours or untilthe reaction is substantially complete. Alternatively, intermediate (XI)can be isolated as a hydrochloride salt, which is treated with betweenand about 1 and about 2 equivalents of aqueous hydrobromic acid toprovide the phenyltropane intermediate (III′).

Intermediate (III′) can be isolated by conventional procedures as a freebase or as a hydrobromide salt. Crystallization of the hydrobromide saltprovides intermediate (III′) with high stereospecificity in the endoconfiguration (endo to exo ratio of greater than 99.1:0.8).

As described in the examples below, certain variations of the aboveprocess can alternatively be used to prepare intermediate (III′). Forexample different reagents can be used to eliminate the hydroxy from(IX) to obtain intermediate (X), which may be isolated as a freebaseinstead of in salt form. In yet another alternative process sequence,treatment of intermediate (IX) with boron tribromide or HBr removes themethyl group as it eliminates the hydroxy substituent.

One process for preparing intermediate (III″) in which the variable R¹is —C(O)NH₂ uses (III′) as a starting material as shown in Scheme E.

where -OTf represents trifluoromethane sulfonate (commonly triflate) andP² represents an amino-protecting group.

For example, when Boc is used as the protecting group, first, thephenyltropane (III′) is typically reacted with about 1 equivalent ofdi-tert-butyl dicarbonate (commonly Boc₂O) to provide the Boc-protectedintermediate (XII). The reactants are typically cooled to about 0° C.and then allowed to warm to ambient temperature over a period of betweenabout 12 and about 24 hours. When tri-fluoroacetyl is used as theprotecting group, typically (III′) is reacted with about 2 equivalentsof tri-fluoroacetyl anhydride to form the protected intermediate (XII).Next, intermediate (XII) in an inert diluent is contacted with a slightexcess, for example about 1.1 equivalents of trifluoromethane sulfonylchloride in the presence of between about 1 and about 2 equivalents ofbase to provide intermediate (XIII), which can be isolated byconventional procedures. Reaction of (XIII) with zinc cyanide in thepresence of a transition metal catalyst, provides intermediate (XIV).This reaction is typically conducted at a temperature between about 60°C. and 120° C. under an inert atmosphere for about 2 to about 12 hoursor until the reaction is substantially complete.

Finally, the nitrile intermediate (XIV) is hydrolyzed and deprotected toprovide the carboxamide intermediate (III″). Typically, in thisreaction, when P² is Boc, intermediate (XIV) in an acidic solvent, forexample trifluoroacetic acid, is contacted with between about 4 andabout 6 equivalents of concentrated sulfuric acid. Typically thereaction is conducted in the temperature range of between about 50° C.and about 80° C. for about 8 to about 24 hours or until the reaction issubstantially complete. The product is typically isolated in freebaseform. Alternatively, the transformation of (XIV) to (III″) is performedin two steps in which, the nitrile substituent of intermediate (XIV) isfirst hydrolyzed to the carboxamide by reaction with potassium carbonateand hydrogen peroxide and then the Boc protecting group is removed bytreatment with acid, e.g. trifluoroacetic acid.

When a tri-fluoroacetyl protecting group is used, the nitrileintermediate is first hydrolyzed to the carboxamide in concentratedsulfuric acid as described above. Quenching of the hydrolysis reactionby addition of base also removes the protecting group. The product istypically isolated as the hydrochloric acid salt. Yet anotheralternative reaction sequence which makes use of a protectedcyanophenyltropane intermediate is described in the examples below.

An intermediate of formula (III) in which R¹ is NHS(O)₂R^(c) can beprepared from intermediate (XIII) of Scheme E. As described, forexample, in Preparation 23 below, an intermediate of formula (III) inwhich R¹ represents —NHS(O)₂CH₃, can be prepared by reactingintermediate (XIII) with benzophenone imine in the presence of apalladium catalyst to provide a 3-aminophenyl substituted protected8-azabicyclooctane intermediate, which, in turn, is reacted withmethanesulfonylchloride to prepare a protected intermediate in which R¹is —NHS(O)₂CH₃. The protecting group is then removed by conventionalmethods, to provide the intermediate of formula (III).

The triflate substituted intermediate (XIII) is also useful as astarting material for the preparation of other key intermediates tocompounds of the inventions. An intermediate of formula (III) in whichR¹ is the ester, —C(O)OR^(a) wherein R^(a) is C₁₋₃alkyl, can be preparedby the palladium catalyzed carbonylation of (XIII) in the presence of analcoholic solvent R^(a)OH followed by a deprotection step. Theintermediate (III) in which R¹ is the acid, —C(O)OH, can be obtained byhydrolysis of the protected form of intermediate (III) in which R¹ isthe ester, in the presence of an inorganic base and subsequentdeprotection. Reduction of the protected acid intermediate, using, forexample a reducing agent such as sodium borohydride, can provide theintermediate of formula (III) in which R¹ is —CH₂OH after deprotection.

Intermediates of formula (IV), used in Scheme B1, can be prepared froman alcohol of formula (XV) as illustrated in process Scheme F:

where G^(a) is defined such that -G^(a)-CH₂ is G and L is a leavinggroup. Alcohol (XV) can be prepared by the process of reaction (i) inwhich an alcohol of the formula H₂N-A-CH₂—OH is reacted with asubstituted alkylhalide of the formula R²-G-L under conditions similarto those described for the reaction of Scheme B2. Alcohol (XV) can alsobe prepared by the process of reaction (ii) under typical acid couplingconditions as described previously, to form the intermediate amide whichis reduced, for example by a borane reduction process, to provide analcohol intermediate of formula (XV). Next, addition of anamino-protecting group by conventional procedures forms intermediate(XVI) which is oxidized to provide an intermediate of formula (IV).Intermediate (IV) can be prepared and stored as a bisulfate adduct, fromwhich the aldehyde is released prior to use.

In an alternate process for the preparation of compounds of theinvention of formula (Ia), the phenyltropane intermediate (III) isreacted with an intermediate of formula (XVII)

under conditions similar to those described for the initial reaction ofScheme B1. When R^(4a) is a protected form of R⁴, a final deprotectionstep is performed to provide compound (Ia). Intermediate (XVII) can beprepared by reaction of the alcohol (XV) with the reagent R^(4a)C(O)-Lto add —C(O)R^(4a) to the nitrogen of (XV), followed by oxidation of theresulting alcohol to the aldehyde (XVII). Urea compounds of theinvention of formula (Ib) may be prepared by processes analogous to thatshown in Scheme G.

Further details regarding specific reaction conditions and otherprocedures for preparing representative compounds of the invention orintermediates thereto are described in the examples below.

Accordingly, in a method aspect, the invention provides a process forpreparing a compound of formula (I), or a salt or protected derivativethereof, the process comprising (a) reacting a compound of formula (II)with (i) a compound of formula R^(4a)C(O)-L or (ii) a compound offormula R⁵—N═C═O; or (b) reacting a compound of formula (III) with acompound of formula (XVII); and, optionally, removing the protectinggroup or groups from R^(4a), to provide a compound of formula (I), or asalt or protected derivative thereof.

In separate aspects, the invention further provides a compound offormula (II) and a compound of formula (III), wherein the variables R¹,R², G, and A take any of the values described in aspects of theinvention disclosed above. In particular, the invention provides acompound of formula (II), wherein R¹ is —C(O)NH₂, R² is cyclohexyl orphenyl wherein cyclohexyl and phenyl are each optionally substitutedwith one or two halo, G is —CH₂— and A is —CH₂—. In addition, in yetanother specific aspect, the invention provides a compound of formula(III) wherein R¹ is —OR^(a) or —C(O)NR^(a)R^(b), or wherein R¹ is —OH or—C(O)NH₂.

Pharmaceutical Compositions

The 8-azabicyclooctane compounds of the invention are typicallyadministered to a patient in the form of a pharmaceutical composition orformulation. Such pharmaceutical compositions may be administered to thepatient by any acceptable route of administration including, but notlimited to, oral, rectal, vaginal, nasal, inhaled, topical (includingtransdermal) and parenteral modes of administration.

Accordingly, in one of its compositions aspects, the invention isdirected to a pharmaceutical composition comprising apharmaceutically-acceptable carrier or excipient and a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof. Optionally, such pharmaceutical compositionsmay contain other therapeutic and/or formulating agents if desired. Whendiscussing compositions, the “compound of the invention” may also bereferred to herein as the “active agent”. As used herein, the term“compound of the invention” is intended to include compounds of formula(I) as well as the species embodied in formula (I′). “Compound of theinvention” includes, in addition, pharmaceutically-acceptable salts andsolvates of the compound unless otherwise indicated.

The pharmaceutical compositions of the invention typically contain atherapeutically effective amount of a compound of the present inventionor a pharmaceutically-acceptable salt thereof. Typically, suchpharmaceutical compositions will contain from about 0.1 to about 95% byweight of the active agent; preferably, from about 5 to about 70% byweight; and more preferably from about 10 to about 60% by weight of theactive agent.

Any conventional carrier or excipient may be used in the pharmaceuticalcompositions of the invention. The choice of a particular carrier orexcipient, or combinations of carriers or excipients, will depend on themode of administration being used to treat a particular patient or typeof medical condition or disease state. In this regard, the preparationof a suitable pharmaceutical composition for a particular mode ofadministration is well within the scope of those skilled in thepharmaceutical arts. Additionally, the carriers or excipients used inthe pharmaceutical compositions of this invention arecommercially-available. By way of further illustration, conventionalformulation techniques are described in Remington: The Science andPractice of Pharmacy, 20^(th) Edition, Lippincott Williams & White,Baltimore, Md. (2000); and H. C. Ansel et al., Pharmaceutical DosageForms and Drug Delivery Systems, 7^(th) Edition, Lippincott Williams &White, Baltimore, Md. (1999).

Representative examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, the following:sugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose, such as microcrystalline cellulose,and its derivatives, such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin;talc; excipients, such as cocoa butter and suppository waxes; oils, suchas peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil,corn oil and soybean oil; glycols, such as propylene glycol; polyols,such as glycerin, sorbitol, mannitol and polyethylene glycol; esters,such as ethyl oleate and ethyl laurate; agar; buffering agents, such asmagnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol; phosphatebuffer solutions; and other non-toxic compatible substances employed inpharmaceutical compositions.

Pharmaceutical compositions are typically prepared by thoroughly andintimately mixing or blending the active agent with apharmaceutically-acceptable carrier and one or more optionalingredients. The resulting uniformly blended mixture can then be shapedor loaded into tablets, capsules, pills and the like using conventionalprocedures and equipment.

The pharmaceutical compositions of the invention are preferably packagedin a unit dosage form. The term “unit dosage form” refers to aphysically discrete unit suitable for dosing a patient, i.e., each unitcontaining a predetermined quantity of active agent calculated toproduce the desired therapeutic effect either alone or in combinationwith one or more additional units. For example, such unit dosage formsmay be capsules, tablets, pills, and the like, or unit packages suitablefor parenteral administration.

In one embodiment, the pharmaceutical compositions of the invention aresuitable for oral administration. Suitable pharmaceutical compositionsfor oral administration may be in the form of capsules, tablets, pills,lozenges, cachets, dragees, powders, granules; or as a solution or asuspension in an aqueous or non-aqueous liquid; or as an oil-in-water orwater-in-oil liquid emulsion; or as an elixir or syrup; and the like;each containing a predetermined amount of a compound of the presentinvention as an active ingredient.

When intended for oral administration in a solid dosage form (i.e., ascapsules, tablets, pills and the like), the pharmaceutical compositionsof the invention will typically comprise the active agent and one ormore pharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate. Optionally or alternatively, such solid dosageforms may also comprise: fillers or extenders, such as starches,microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and/orsilicic acid; binders, such as carboxymethylcellulose, alginates,gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, suchas glycerol; disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and/or sodium carbonate; solution retarding agents, such as paraffin;absorption accelerators, such as quaternary ammonium compounds; wettingagents, such as cetyl alcohol and/or glycerol monostearate; absorbents,such as kaolin and/or bentonite clay; lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, and/or mixtures thereof; coloring agents; and buffering agents.

Release agents, wetting agents, coating agents, sweetening, flavoringand perfuming agents, preservatives and antioxidants can also be presentin the pharmaceutical compositions of the invention. Examples ofpharmaceutically-acceptable antioxidants include: water-solubleantioxidants, such as ascorbic acid, cysteine hydrochloride, sodiumbisulfate, sodium metabisulfate, sodium sulfite and the like;oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole, butylated hydroxytoluene, lecithin, propyl gallate,alpha-tocopherol, and the like; and metal-chelating agents, such ascitric acid, ethylenediamine tetraacetic acid, sorbitol, tartaric acid,phosphoric acid, and the like. Coating agents for tablets, capsules,pills and like, include those used for enteric coatings, such ascellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylic acid!methacrylic acid estercopolymers, cellulose acetate trimellitate, carboxymethyl ethylcellulose, hydroxypropyl methyl cellulose acetate succinate, and thelike.

Pharmaceutical compositions of the invention may also be formulated toprovide slow or controlled release of the active agent using, by way ofexample, hydroxypropyl methyl cellulose in varying proportions; or otherpolymer matrices, liposomes and/or microspheres. In addition, thepharmaceutical compositions of the invention may optionally containopacifying agents and may be formulated so that they release the activeingredient only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active agent can also be in micro-encapsulated form, ifappropriate, with one or more of the above-described excipients.

Suitable liquid dosage forms for oral administration include, by way ofillustration, pharmaceutically-acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. Liquid dosage formstypically comprise the active agent and an inert diluent, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (esp., cottonseed, groundnut, corn, germ, olive, castor andsesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan, and mixtures thereof. Suspensions, inaddition to the active ingredient, may contain suspending agents suchas, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

The compounds of this invention can also be administered parenterally(e.g. by intravenous, subcutaneous, intramuscular or intraperitonealinjection). For parenteral administration, the active agent is typicallyadmixed with a suitable vehicle for parenteral administration including,by way of example, sterile aqueous solutions, saline, low molecularweight alcohols such as propylene glycol, polyethylene glycol, vegetableoils, gelatin, fatty acid esters such as ethyl oleate, and the like.Parenteral formulations may also contain one or more anti-oxidants,solubilizers, stabilizers, preservatives, wetting agents, emulsifiers,buffering agents, or dispersing agents. These formulations may berendered sterile by use of a sterile injectable medium, a sterilizingagent, filtration, irradiation, or heat.

Alternatively, the pharmaceutical compositions of the invention areformulated for administration by inhalation. Suitable pharmaceuticalcompositions for administration by inhalation will typically be in theform of an aerosol or a powder. Such compositions are generallyadministered using well-known delivery devices, such as a metered-doseinhaler, a dry powder inhaler, a nebulizer or a similar delivery device.

When administered by inhalation using a pressurized container, thepharmaceutical compositions of the invention will typically comprise theactive ingredient and a suitable propellant, such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas.Additionally, the pharmaceutical composition may be in the form of acapsule or cartridge (made, for example, from gelatin) comprising acompound of the invention and a powder suitable for use in a powderinhaler. Suitable powder bases include, by way of example, lactose orstarch.

The compounds of the invention can also be administered transdermallyusing known transdermal delivery systems and excipients. For example,the active agent can be admixed with permeation enhancers, such aspropylene glycol, polyethylene glycol monolaurate, azacycloalkan-2-onesand the like, and incorporated into a patch or similar delivery system.Additional excipients including gelling agents, emulsifiers and buffers,may be used in such transdermal compositions if desired.

If desired, the compounds of this invention may be administered incombination with one or more other therapeutic agents. In thisembodiment, a compound of this invention is either physically mixed withthe other therapeutic agent to form a composition containing bothagents; or each agent is present in separate and distinct compositionswhich are administered to the patient simultaneously or sequentially.

For example, a compound of formula I can be combined with secondtherapeutic agent using conventional procedures and equipment to form acomposition comprising a compound of formula I and a second therapeuticagent. Additionally, the therapeutic agents may be combined with apharmaceutically acceptable carrier to form a pharmaceutical compositioncomprising a compound of formula I, a second therapeutic agent and apharmaceutically acceptable carrier. In this embodiment, the componentsof the composition are typically mixed or blended to create a physicalmixture. The physical mixture is then administered in a therapeuticallyeffective amount using any of the routes described herein.Alternatively, the therapeutic agents may remain separate and distinctbefore administration to the patient. In this embodiment, the agents arenot physically mixed together before administration but are administeredsimultaneously or at separate times as separate compositions. Suchcompositions can be packaged separately or may be packaged together as akit. The two therapeutic agents in the kit may be administered by thesame route of administration or by different routes of administration.

Any therapeutic agent compatible with the compounds of the presentinvention may be used as the second therapeutic agent. In particular,prokinetic agents acting via mechanisms other than mu opioid receptorantagonism may be used in combination with the present compounds. Forexample, 5-HT₄ receptor agonists, such as tegaserod, renzapride,mosapride, prucalopride, 1-isopropyl-1H-indazole-3-carboxylic acid{(1S,3R,5R)-8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide,1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid{(1S,3R,5R)-8-[(R)-2-hydroxy-3-(methanesulfonyl-methyl-amino)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide,or4-(4-{[(2-isopropyl-1H-benzoimidazole-4-carbonyl)amino]methyl}-piperidin-1-ylmethyl)piperidine-1-carboxylicacid methyl ester may be used as the second therapeutic agent.

Additional useful prokinetic agents include, but are not limited to,5-HT₃ receptor agonists (e.g. pumosetrag), 5-HT_(1A) receptorantagonists (e.g. AGI 001), alpha-2-delta ligands (e.g. PD-217014),chloride channel openers (e.g. lubiprostone), dopamine antagonists (e.g.itopride, metaclopramide, domperidone), GABA-B agonists (e.g. baclofen,AGI 006), kappa opioid agonists (e.g. asimadoline), muscarinic M₁ and M₂antagonists (e.g. acotiamide), motilin agonists (e.g. mitemcinal),guanylate cyclase activators (e.g. MD-1100) and ghrelin agonists (e.g.Tzp 101, RC 1139).

In addition, the compounds of the invention can be combined with opioidtherapeutic agents. Such opioid agents include, but are not limited to,morphine, pethidine, codeine, dihydrocodeine, oxycontin, oxycodone,hydrocodone, sufentanil, fentanyl, remifentanil, buprenorphine,methadone, and heroin.

Numerous additional examples of such therapeutic agents are known in theart and any such known therapeutic agents may be employed in combinationwith the compounds of this invention. Secondary agent(s), when included,are present in a therapeutically effective amount, i.e. in any amountthat produces a therapeutically beneficial effect when co-administeredwith a compound of the invention. Suitable doses for the othertherapeutic agents administered in combination with a compound of theinvention are typically in the range of about 0.05 μg/day to about 100mg/day.

Accordingly, the pharmaceutical compositions of the invention optionallyinclude a second therapeutic agent as described above.

The following examples illustrate representative pharmaceuticalcompositions of the present invention:

Formulation Example A: Hard Gelatin Capsules for Oral Administration

A compound of the invention (50 g), spray-dried lactose (200 g) andmagnesium stearate (10 g) are thoroughly blended. The resultingcomposition is loaded into a hard gelatin capsule (260 mg of compositionper capsule).

Formulation Example B: Hard Gelatin Capsules for Oral Administration

A compound of the invention (20 mg), starch (89 mg), microcrystallinecellulose (89 mg), and magnesium stearate (2 mg) are thoroughly blendedand then passed through a No. 45 mesh U.S. sieve. The resultingcomposition is loaded into a hard gelatin capsule (200 mg of compositionper capsule).

Formulation Example C: Gelatin Capsules for Oral Administration

A compound of the invention (10 mg), polyoxyethylene sorbitan monooleate(50 mg), and starch powder (250 mg) are thoroughly blended and thenloaded into a gelatin capsule (310 mg of composition per capsule).

Formulation Example D: Tablets for Oral Administration

A compound of the invention (5 mg), starch (50 mg), andmicroscrystalline cellulose (35 mg) are passed through a No. 45 meshU.S. sieve and mixed thoroughly. A solution of polyvinylpyrrolidone (10wt % in water, 4 mg) is mixed with the resulting powders, and thismixture is then passed through a No. 14 mesh U.S. sieve. The granules soproduced are dried at 50-60EC and passed through a No. 18 mesh U.S.sieve. Sodium carboxymethyl starch (4.5 mg), magnesium stearate (0.5 mg)and talc (1 mg), which have previously been passed through a No. 60 meshU.S. sieve, are then added to the granules. After mixing, the mixture iscompressed on a tablet machine to afford a tablet weighing 100 mg.

Formulation Example E: Tablets for Oral Administration

A compound of the invention (25 mg), microcrystalline cellulose (400mg), fumed silicon dioxide (10 mg), and stearic acid (5 mg) arethoroughly blended and then compressed to form tablets (440 mg ofcomposition per tablet).

Formulation Example F: Single-Scored Tablets for Oral Administration

A compound of the invention (15 mg), cornstarch (50 mg), croscarmellosesodium (25 mg), lactose (120 mg), and magnesium stearate (5 mg) arethoroughly blended and then compressed to form single-scored tablet (215mg of compositions per tablet).

Formulation Example G: Suspension for Oral Administration

The following ingredients are thoroughly mixed to form a suspension fororal administration containing 100 mg of active ingredient per 10 mL ofsuspension:

Ingredients Amount Compound of the invention 0.1 g Fumaric acid 0.5 gSodium chloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 gGranulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum k(Vanderbilt Co.) 1.0 g Flavoring 0.035 mL Colorings 0.5 mg Distilledwater q.s. to 100 mL

Formulation Example H: Dry Powder Composition

A micronized compound of the invention (1 mg) is blended with lactose(25 mg) and then loaded into a gelatin inhalation cartridge. Thecontents of the cartridge are administered using a powder inhaler.

Formulation Example J: Injectable Formulation

A compound of the invention (0.1 g) is blended with 0.1 M sodium citratebuffer solution (15 mL). The pH of the resulting solution is adjusted topH 6 using 1 N aqueous hydrochloric acid or 1 N aqueous sodiumhydroxide. Sterile normal saline in citrate buffer is then added toprovide a total volume of 20 mL.

It will be understood that any form of the compounds of the invention,(i.e. free base, pharmaceutical salt, or solvate) that is suitable forthe particular mode of administration, can be used in the pharmaceuticalcompositions discussed above.

Utility

The 8-azabicyclooctane compounds of the invention are antagonists at themu opioid receptor and therefore are expected to be useful for treatingmedical conditions mediated by mu opioid receptors or associated with muopioid receptor activity, i.e. medical conditions which are amelioratedby treatment with a mu opioid receptor antagonist. In particular, thecompounds of the invention are expected to be useful for treatingadverse effects associated with use of opioid analgesics, i.e. symptomssuch as constipation, decreased gastric emptying, abdominal pain,bloating, nausea, and gastroesophageal reflux, termed collectivelyopioid-induced bowel dysfunction. The mu opioid receptor antagonists ofthe invention are also expected to be useful for treating post-operativeileus, a disorder of reduced motility of the gastrointestinal tract thatoccurs after abdominal or other surgery. In addition, it has beensuggested that mu opioid receptor antagonist compounds may be used forreversing opioid-induced nausea and vomiting. Further, those mu opioidreceptor antagonists exhibiting some central penetration may be usefulin the treatment of dependency on, or addiction to, narcotic drugs,alcohol, or gambling, or in preventing, treating, and/or amelioratingobesity.

Since compounds of the invention increase motility of thegastrointestinal (GI) tract in animal models, the compounds are expectedto be useful for treating disorders of the GI tract caused by reducedmotility in mammals, including humans. Such GI motility disordersinclude, by way of illustration, chronic constipation,constipation-predominant irritable bowel syndrome (C-IBS), diabetic andidiopathic gastroparesis, and functional dyspepsia.

In one aspect, therefore, the invention provides a method of increasingmotility of the gastrointestinal tract in a mammal, the methodcomprising administering to the mammal a therapeutically effectiveamount of a pharmaceutical composition comprising apharmaceutically-acceptable carrier and a compound of the invention.

When used to treat disorders of reduced motility of the GI tract orother conditions mediated by mu opioid receptors, the compounds of theinvention will typically be administered orally in a single daily doseor in multiple doses per day, although other forms of administration maybe used. For example, particularly when used to treat post-operativeileus, the compounds of the invention may be administered parenterally.The amount of active agent administered per dose or the total amountadministered per day will typically be determined by a physician, in thelight of the relevant circumstances, including the condition to betreated, the chosen route of administration, the actual compoundadministered and its relative activity, the age, weight, and response ofthe individual patient, the severity of the patient's symptoms, and thelike.

Suitable doses for treating disorders of reduced motility of the GItract or other disorders mediated by mu opioid receptors will range fromabout 0.0007 to about 20 mg/kg/day of active agent, including from about0.0007 to about 1.4 mg/kg/day. For an average 70 kg human, this wouldamount to from about 0.05 to about 100 mg per day of active agent.

In one aspect of the invention, the compounds of the invention are usedto treat opioid-induced bowel dysfunction. When used to treatopioid-induced bowel dysfunction, the compounds of the invention willtypically be administered orally in a single daily dose or in multipledoses per day. Preferably, the dose for treating opioid-induced boweldysfunction will range from about 0.05 to about 100 mg per day.

In another aspect of the invention, the compounds of the invention areused to treat post-operative ileus. When used to treat post-operativeileus, the compounds of the invention will typically be administeredorally or intravenously in a single daily dose or in multiple doses perday. Preferably, the dose for treating post-operative ileus will rangefrom about 0.05 to about 100 mg per day.

The invention also provides a method of treating a mammal having adisease or condition associated with mu opioid receptor activity, themethod comprising administering to the mammal a therapeuticallyeffective amount of a compound of the invention or of a pharmaceuticalcomposition comprising a compound of the invention.

As described above, compounds of the invention are mu opioid receptorantagonists. The invention further provides, therefore, a method ofantagonizing a mu opioid receptor in a mammal, the method comprisingadministering a compound of the invention to the mammal.

The mu opioid receptor antagonists of the invention are optionallyadministered in combination with another therapeutic agent or agents, inparticular, in combination with prokinetic agents acting via non-muopioid mechanisms. Accordingly, in another aspect, the methods andcompositions of the invention further comprise a therapeuticallyeffective amount of another prokinetic agent.

In addition, the compounds of the invention are also useful as researchtools for investigating or studying biological systems or samples havingmu opioid receptors, or for discovering new compounds having mu opioidreceptor activity. Any suitable biological system or sample having muopioid receptors may be employed in such studies which may be conductedeither in vitro or in vivo. Representative biological systems or samplessuitable for such studies include, but are not limited to, cells,cellular extracts, plasma membranes, tissue samples, mammals (such asmice, rats, guinea pigs, rabbits, dogs, pigs, etc.) and the like. Theeffects of contacting a biological system or sample comprising a muopioid receptor with a compound of the invention are determined usingconventional procedures and equipment, such as the radioligand bindingassay and functional assay described herein or other functional assaysknown in the art. Such functional assays include, but are not limitedto, ligand-mediated changes in intracellular cyclic adenosinemonophosphate (cAMP), ligand-mediated changes in activity of the enzymeadenylyl cyclase, ligand-mediated changes in incorporation of analogs ofguanosine triphosphate (GTP), such as [³⁵S]GTPγS (guanosine5′-O-(γ-thio)triphosphate) or GTP-Eu, into isolated membranes viareceptor catalyzed exchange of GTP analogs for GDP analogs, andligand-mediated changes in free intracellular calcium ions. A suitableconcentration of a compound of the invention for such studies typicallyranges from about 1 nanomolar to about 500 nanomolar.

When using compounds of the invention as research tools for discoveringnew compounds have mu opioid receptor activity, binding or functionaldata for a test compound or a group of test compounds is compared to themu opioid receptor binding or functional data for a compound of theinvention to identify test compounds that have superior binding orfunctional activity, if any. This aspect of the invention includes, asseparate embodiments, both the generation of comparison data (using theappropriate assays) and the analysis of the test data to identify testcompounds of interest.

Among other properties, compounds of the invention have been found toexhibit potent binding to mu opioid receptors and little or no agonismin mu receptor functional assays. Therefore, the compounds of theinvention are potent mu opioid receptor antagonists. Further, compoundsof the invention have demonstrated predominantly peripheral activity ascompared with central nervous system activity in animal models.Therefore, these compounds can be expected to reverse opioid-inducedreductions in GI motility without interfering with the beneficialcentral effects of analgesia. These properties, as well as the utilityof the compounds of the invention, can be demonstrated using various invitro and in vivo assays well-known to those skilled in the art.Representative assays are described in further detail in the followingexamples.

EXAMPLES

The following synthetic and biological examples are offered toillustrate the invention, and are not to be construed in any way aslimiting the scope of the invention. In the examples below, thefollowing abbreviations have the following meanings unless otherwiseindicated. Abbreviations not defined below have their generally acceptedmeanings.

-   Boc=tert-butoxycarbonyl-   (Boc)₂O=di-tert-butyl dicarbonate-   DABCO=1,4-diazaobicylco[2,2,2]octane triethylenediamine-   DCM=dichloromethane-   DIPEA=N,N-diisopropylethylamine-   DMA=dimethylacetamide-   DMAP=dimethylaminopyridine-   DMF=N,N-dimethylformamide-   DMSO=dimethyl sulfoxide-   EtOAc=ethyl acetate-   EtOH=ethanol-   HATU=N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium    hexafluorophosphate-   MeCN=acetonitrile-   MeOH=methanol-   MeTHF=2-methyltetrahydrofuran-   MTBE=tert-butyl methyl ether-   PyBop=benzotriazol-1-yloxytripyrrolidino-phosphonium    hexafluorophosphate-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran

Reagents (including secondary amines) and solvents were purchased fromcommercial suppliers (Aldrich, Fluka, Sigma, etc.), and used withoutfurther purification. Reactions were run under nitrogen atmosphere,unless noted otherwise. Progress of reaction mixtures was monitored bythin layer chromatography (TLC), analytical high performance liquidchromatography (anal. HPLC), and mass spectrometry, the details of whichare given below and separately in specific examples of reactions.Reaction mixtures were worked up as described specifically in eachreaction; commonly they were purified by extraction and otherpurification methods such as temperature-, and solvent-dependentcrystallization, and precipitation. In addition, reaction mixtures wereroutinely purified by preparative HPLC: a general protocol is describedbelow. Characterization of reaction products was routinely carried outby mass and ¹H-NMR spectrometry. For NMR measurement, samples weredissolved in deuterated solvent (CD₃OD, CDCl₃, or DMSO-d₆), and ¹H-NMRspectra were acquired with a Varian Gemini 2000 instrument (300 MHz)under standard observation conditions. Mass spectrometric identificationof compounds was performed by an electrospray ionization method (ESMS)with an Applied Biosystems (Foster City, Calif.) model API 150 EXinstrument or an Agilent (Palo Alto, Calif.) model 1100 LC/MSDinstrument.

Preparation 1: Synthesis of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-phenola. Preparation of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one

A mixture of 2,5-dimethoxy tetrahydrofuran (20.5 g, 155.1 mmol), water(42.5 mL) and concentrated HCl (30 mL) was stirred at room temperaturefor about 30 minutes. To this stirring mixture was sequentially addedwater (62.5 mL), a premixed solution of benzylamine (17.9 mL, 162.9mmol), water (87.5 mL) and concentrated HCl (23 mL), a premixed solutionof 1,3-acetonedicarboxylic acid (25 g) and water (100 mL), and asolution of Na₂HPO₄ (16.5 g) in water (50 mL). The resulting mixture wasadjusted to pH 4 to 5 with 40% aqueous NaOH and stirred overnight atroom temperature. The mixture was acidified to pH 3 with concentratedHCl and heated to 85° C. for 3 hours. After cooling to room temperature,the mixture was basified with 20% aqueous NaOH, saturated with solidsodium chloride and extracted with dichloromethane. The organic layerwas washed with brine, dried over sodium sulfate, filtered andconcentrated to give a dark oil which was purified by flash columnchromatography. The product was eluted with 20% ethyl acetate/hexanes.Desired fractions were combined and concentrated to give the titleintermediate as a yellowish oil (16.17 g).

b. Preparation of8-benzyl-3-exo-(3-methoxy-phenyl)-8-azabicyclo[3.2.1]octan-3-ol

A solution of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (7.28 g, 33.8mmol) in dry THF (113 mL) was cooled to −78° C. under nitrogen. To thiscold solution was added a 1.0 M solution of 3-methoxyphenyl magnesiumbromide in THF (44 mL) via a dropping funnel. The resulting mixture waswarmed to room temperature and stirred for about 20 minutes. Thereaction was cooled to 0° C. and additional 3-methoxyphenyl magnesiumbromide (30 mL, 30.0 mmol) in THF was added. The reaction was warmed toroom temperature again after addition and stirred for 30 minutes. Thereaction was quenched with saturated ammonium chloride and the productextracted with ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate, filtered and concentrated. The residue waspurified by column chromatography and eluted with 5% (200 mL), 10% (200mL), 15% (200 mL), 20% (200 mL), 30% (200 mL), and 100% ethylacetate/hexanes. Desired fractions were combined and concentrated togive the title intermediate as a light yellowish oil (4.0 g). Startingmaterial (3.87 g) was recovered. (m/z): [M+H]⁺ calcd for C₂₁H₂₅NO₂324.20; found, 324.5.

c. Preparation of 3-(8-benzyl-8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-phenol

To a solution of8-benzyl-3-endo-(3-methoxy-phenyl)-8-azabicyclo[3.2.1]octan-3-ol (4.65g, 14.4 mmol) in dichloromethane (70 mL) at 0° C. was added 1.0 M borontribromide in dichloromethane (28 mL). The resulting mixture was stirredat 0° C. for one hour then allowed to warm to room temperature andstirred at that temperature overnight. The reaction mixture wasconcentrated and co-evaporated with methanol three times. The resultingresidue was dissolved in 50% acetic acid in water (20 mL), filtered, andpurified by reverse phase preparative HPLC to give the TFA salt of thetitle compound (4.6 g). (m/z): [M+H]⁺ calcd for C₂₀H₂₁NO, 292.17; found,292.3.

d. Synthesis of 3-endo-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol

To a solution of the TFA salt of3-(8-benzyl-8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-phenol (2.0 g) in ethanol(200 mL) at room temperature was added palladium hydroxide on carbon (50wt % water, 20% w/w on carbon, 800 mg). The resulting suspension wasdegassed and treated overnight under a hydrogen atmosphere. The reactionmixture was filtered through Celite and rinsed with ethanol. Thefiltrate was concentrated to give the TFA salt of the title compound(1.2 g). (m/z): [M+H]⁺ calcd for C₁₃H₁₇NO, 204.14. found, 204.3.

Preparation 2: Synthesis of3-endo-[8-(2-benzylamino-ethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-phenol a.Preparation of3-endo-[8-(2,2-dimethoxyethyl)-8-azabicyclo[3.2.1]oct-3-yl]phenol

To a stirred suspension of 3-endo-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol(2.0 g, 6.3 mmol) in CH₂Cl₂ (25 mL) at room temperature was addedsequentially N,N-diisopropylethylamine (814 mg, 6.3 mmol),2,2-dimethoxyacetaldehyde (1.31 g, 12.6 mmol) and sodiumtriacetoxyborohydride (1.73 g, 8.19 mmol). The resulting mixture wassonicated to aid dissolution and stirred at room temperature for 30minutes. The reaction was diluted with dichloromethane. The organiclayer was washed with saturated sodium bicarbonate followed by brine,dried over sodium sulfate, filtered, and concentrated to give ayellowish oil, which was used directly in the next step withoutpurification. (m/z): [M+H]⁺ calcd for C₁₇H₂₅NO₃ 292.19; found, 292.3.

b. Preparation of[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-acetaldehyde

The oily product of the previous step was treated with 6N aq HCl (30 mL)at room temperature for two days. Solvents were removed under vacuum.The residue was then dissolved in water and freeze dried to give thetitle intermediate as its HCl salt (1.3 g). (m/z): [M+H]⁺ calcd forC₁₅H₁₉NO₂ 246.15; found, 246.1.

c. Synthesis of3-endo-[8-(2-benzylaminoethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-phenol

To a stirred solution of the HCl salt of[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-acetaldehyde(384 mg, 1.36 mmol) in dichloromethane (4.5 mL) at room temperature wasadded sodium triacetoxyborohydride (374 mg, 1.76 mmol) followed byN,N-diisopropylethylamine (176 mg, 1.36 mmol) and benzylamine (175 mg,1.63 mmol). The solution was stirred at room temperature for 30 minutes,and the reaction was quenched with saturated sodium bicarbonate. Theaqueous layer was extracted with dichloromethane. The resulting organiclayer was washed with brine, dried over sodium sulfate, filtered andconcentrated to give a oily residue. The residue was redissolved in 50%acetic acid in water, filtered and purified by reverse phase preparativeHPLC to give the title compound as its bis TFA salt (191 mg). (m/z):[M+H]⁺ calcd for C₂₂H₂₈N₂O, 337.23; found, 337.3.

Preparation 3

Following the method of Preparation 2, step c, substituting theappropriate amine reagent for benzylamine, the bis TFA salts of thefollowing compounds were prepared:

3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}phenol;(m/z): [M+H]⁺ calcd for C₂₂H₃₄N₂O, 343.28; found, 343.5.

3-endo-{8-[2-(3-fluorobenzylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-phenol;(m/z): [M+H]⁺ calcd for C₂₂H₂₇FN₂O, 355.22; found, 355.5.

3-endo-{8-[2-(2,6-difluorobenzylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-phenol;(m/z): [M+H]⁺ calcd for C₂₂H₂₆F₂N₂O, 373.21; found, 373.3.

3-endo-{8-[2-(4-fluorobenzylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-phenol;(m/z): [M+H]⁺ calcd for C₂₂H₂₇FN₂O, 355.22; found, 355.3.

3-endo-{8-[2-(4-chlorobenzylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-phenol;(m/z): [M+H]⁺ calcd for C₂₂H₂₇ClN₂O, 371.19; found, 371.4.

Preparation 4: Synthesis of 3-endo-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenola. Preparation of trifluoro-methanesulfonic acid8-benzyl-8-aza-bicyclo[3.2.1]oct-2-en-3-yl ester

To a solution of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (12.8 g, 59.5mmol) in anhydrous tetrahydrofuran (200 mL) at −78° C. was added a 1.0 Msolution of sodium hexamethyldisilazane (77 mL, 77.4 mmol) in THFdropwise. The resulting mixture was stirred at −78° C. for thirtyminutes before a THF solution (100 mL) ofN-phenyltrifluoromethanesulfonimide (PhNHTf₂) (25 g, 69.9 mmol) wasadded. After about forty minutes, thin layer chromatography indicatedthe reaction was not complete. Additional PhNTf₂ (2.0 g) in THF wasadded. After 30 minutes, the reaction was quenched with saturatedammonium chloride. The layers were separated and the organic layer waswashed with saturated ammonium chloride twice, followed by brine, driedover sodium sulfate, filtered, and concentrated. The residue was furtherpurified by flash chromatography and eluted with 0% (500 mL) to 5% (500mL) to 10% (500 mL) to 15% (500 mL) to 20% (100 mL) ethylacetate/hexanes. Desired fractions were combined and concentrated togive a yellowish oil (25.6 g, contaminated withN-phenyltrifluoro-methanesulfonamide (PhNHTf). (m/z): [M+H]⁺ calcd forC₁₅H₁₆F₃NO₃S, 348.09; found, 348.0.

b. Preparation of8-benzyl-3-(3-benzyloxyphenyl)-8-azabicyclo[3.2.1]oct-2-ene

To a solution of the product of the previous step (24.6 g, contaminatedwith PhNHTf) in THF (120 mL) and DMA (120 mL) at room temperature wasadded 3-benzyloxyphenylboronic acid (16.46 g), potassium carbonate (19.9g) and tetrakis(triphenylphosphine)palladium(0) (5.0 g). The resultingmixture was degassed, flushed with nitrogen and then stirred undernitrogen atmosphere overnight. The reaction mixture was filtered througha pad of Celite and the filtrate was concentrated to give a dark thickoil which was purified by flash chromatography (and eluted with 40%ethyl acetate in hexanes) to yield the title intermediate (6.9 g).(m/z): [M+H]⁺ calcd for C₂₇H₂₇NO, 382.22; found 382.5.

c. Preparation of 3-endo-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol

To palladium hydroxide (3.5 g, 20% w/w on carbon) was added the productof the previous step (6.9 g) in ethanol (50 mL). The slurry was stirredvigorously under a hydrogen atmosphere for 12 hours. The reactionmixture was filtered through a plug of Celite and the filtrate wasconcentrated to afford the title intermediate (5.6 g). (m/z): [M+H]⁺calcd for C₁₃H₁₇NO, 204.14; found 204.3.

d. Preparation of3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester

The product of the previous step (5.6 g) was dissolved intetrahydrofuran (75 mL) followed by the addition ofN,N-diisopropylethylamine (3.6 mL). To the stirring solution,di-tert-butyl dicarbonate (5.4 g) dissolved in THF (20 mL) was addeddropwise and the reaction was stirred for 1 hour. The reaction wasquenched with methanol, concentrated under vacuum, diluted withdichloromethane (100 mL) and washed with 1.0 N HCl (100 mL), followed bysaturated aqueous sodium chloride (100 mL). The organic layer wastreated with anhydrous sodium sulfate and the solvent was dried undervacuum. The crude product was purified by flash chromatography (andeluted with 20% ethyl acetate in hexanes) to yield crude titleintermediate (3.4 g). The resulting solid was dissolved with ethylacetate (10 mL) and heated to 50° C., followed by the addition ofheptane (50 mL). The solution was allowed to cool to room temperatureover 2 hours. The resulting crystals were filtered to give the titleintermediate (2.2 g).

e. Synthesis of 3-endo-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol

3-endo-(3-Hydroxyphenyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester (2.5 g) was treated with dichloromethane (10 mL) andTFA (10 mL) at room temperature for 10 minutes. The reaction mixture wasconcentrated, co-evaporated with ethyl acetate four times to give awhite solid, and dried under vacuum to give the title compound as itsTFA salt (3.5 g). (m/z): [M+H]⁺ calcd for C₁₃H₁₇NO, 204.14; found 204.3.

Preparation 5: Synthesis of3-endo-(8-azabicyclo[3.2.1]oct-3-yl)benzamide a. Preparation of8-benzyl-3-exo-(3-bromophenyl)-8-azabicyclo[3.2.1]octan-3-ol

To a solution of 1,3-dibromobenzene (7.4 g, 31.3 mmol) in anhydrous THF(80 mL) at −78° C. under nitrogen was added a solution of 1.6Mn-butyllithium in hexanes (20 mL, 31.4 mmol) dropwise. The resultingmixture was stirred at −78° C. for 30 minutes before a solution of8-benzyl-8-azabicyclo[3.2.1]octan-3-one (4.5 g, 20.9 mmol) in anhydrousTHF (20 mL) was added dropwise. The reaction mixture was allowed toslowly warm to −40° C. over one hour and then to room temperature over30 minutes. The reaction was quenched with saturated aqueous NH₄Cl andextracted with ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate, filtered, concentrated, and further purifiedby flash chromatography. The product was eluted with 20% (300 mL) to 30%(600 mL) ethyl acetate/hexanes. Desired fractions were combined andconcentrated to give the title intermediate as a yellowish oil (6.1 g).(m/z): [M+H]⁺ calcd for C₂₀H₂₂BrNO, 372.10; found 372.3, 374.2(isotope).

b. Preparation of3-exo-(8-benzyl-3-hydroxy-8-azabicyclo[3.2.1]oct-3-yl)-benzonitrile

To a solution of the product of the previous step (6.1 g, 16.4 mmol) inanhydrous DMF (82 mL) was added zinc cyanide (2.89 g, 24.6 mmol). Thesuspension was degassed and flushed with nitrogen beforetetrakis(triphenylphosphine)palladium(0) (2.84 g, 2.5 mmol) was added.The resulting reaction mixture was then heated to 85° C. under anitrogen atmosphere overnight. The reaction mixture was cooled to roomtemperature, filtered through Celite and rinsed with ethyl acetate. Theorganic layer was then washed with water three times. The aqueous layerwas back extracted with ethyl acetate. The organic layers were combinedand concentrated to about 25 mL and then extracted four times withaqueous 1N HCl. Combined aqueous layers were back extracted with diethylether twice and then basified to pH 10 with NaOH (pellet). The basicsolution was extracted three times with ethyl acetate. The organiclayers were combined and washed with brine, dried over Na₂SO₄, filteredand concentrated to give the title intermediate as a yellowish oil (4.0g). (m/z): [M+H]⁺ calcd for C₂₁H₂₂N₂O, 319.18. found 319.3.

c. Preparation of3-exo-(8-benzyl-3-hydroxy-8-azabicyclo[3.2.1]oct-3-yl)-benzamide

To a solution of3-exo-(8-benzyl-3-hydroxy-8-azabicyclo[3.2.1]oct-3-yl)-benzonitrile(3.74 g, 11.76 mmol) in DMSO (80 mL) at room temperature was addedpotassium carbonate (243 mg) followed by 30% aqueous hydrogen peroxide(6 mL) dropwise. The reaction progress was monitored by massspectrometry. After about 2.5 hr, the reaction was complete. Thereaction was quenched with water (140 mL). The aqueous layer wasextracted three times with ethyl acetate. The organic layers werecombined and washed with half saturated brine (5×40 mL) or until aniodine starch test strip indicated no remaining peroxide. The organiclayer was washed with brine, dried over sodium sulfate, filtered, andconcentrated to give the title intermediate as a white solid (3.15 g).(m/z): [M+H]⁺ calcd for C₂₁H₂₄N₂O₂ 337.19; found 337.3.

d. Preparation of 3-(8-benzyl-8-azabicyclo[3.2.1]oct-2-en-3-yl)benzamide

The product of the previous step (3.15 g) was treated with TFA (30 mL)at 75° C. for four hours. After concentration, the residue was dissolvedin 50% acetic acid in water (15 mL), filtered, and purified by reversedphase preparative HPLC to give the TFA salt of the title intermediate asa white solid. (m/z): [M+H]⁺ calcd for C₂₁H₂₂N₂O, 319.18. found 319.3.

e. Synthesis of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-benzamide

The TFA salt of3-endo-(8-benzyl-8-azabicyclo[3.2.1]oct-2-en-3-yl)benzamide (3.0 g) wasdissolved in ethanol (50 mL) at room temperature and treated withpalladium hydroxide on carbon (50 wt % water, 20% Pd on dry base, 300mg). The resulting suspension was degassed and flushed with nitrogenthree times and then exposed to a hydrogen atmosphere overnight. Thereaction mixture was filtered through Celite and rinsed with ethanol.The filtrate was concentrated to give a light yellowish oil which turnedinto a foam upon drying under vacuum to give the title compound as itsTFA salt (2.2 g). (m/z): [M+H]⁺ calcd for C₁₄H₁₈N₂O, 231.15; found231.3.

Preparation 6: Synthesis of3-endo-[8-(2-benzylaminoethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]benzamide a.Preparation of3-endo-[8-(2,2-dimethoxyethyl)-8-azabicyclo[3.2.1]oct-3-yl]-benzamide

To a solution of the TFA salt of3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-benzamide, prepared according tothe method of Preparation 5 (1.03 g, 2.98 mmol) in dichloromethane (15.0mL) at room temperature was added N,N-diisopropylethylamine (385 mg,2.98 mmol) followed by 2,2-dimethoxy-acetaldehyde (621 mg, 5.96 mmol)and sodium triacetoxyborohydride (821 mg, 3.87 mmol). The resultingmixture was sonicated to aid dissolution. After about 30 minutes, thereaction was concentrated. The resulting residue was co-evaporated withmethanol twice and then dissolved in 50% acetic acid in water (10 mL),filtered and purified by reverse phase preparative HPLC to give thetitle intermediate as its TFA salt (577 mg). (m/z): [M+H]⁺ calcd forC₁₈H₂₆N₂O₃ 319.20. found 319.3.

b. Preparation of3-endo-[8-(2-oxo-ethyl)-8-azabicyclo[3.2.1]oct-3-yl]benzamide

The product of the previous step (577 mg) was treated with 6N HCl (20mL) at room temperature overnight. The reaction mixture was concentratedand the residue was diluted with water and freeze dried to give thetitle intermediate as its HCl salt (554 mg). (m/z): [M+H]⁺ calcd forC₁₆H₂₀N₂O₂ 273.16; found 273.1.

c. Synthesis of3-endo-[8-(2-benzylaminoethyl)-8-azabicyclo[3.2.1]oct-3-yl]-benzamide

To a slurry of the HCl salt of3-endo-[8-(2-oxo-ethyl)-8-azabicyclo[3.2.1]oct-3-yl]benzamide (220 mg,0.71 mmol) in a mixture of dichloromethane (3 mL) and DMF (1 mL) at roomtemperature was added sodium triacetoxyborohydride (196 mg, 0.92 mmol)followed by benzylamine (91 mg, 0.85 mmol) and N,N-diisopropylethylamine(92 mg, 0.71 mmol). Thirty minutes later, mass spectrometry (electronspray) indicated the reaction was complete. The reaction mixture wasdiluted with dichloromethane. The organic layer was washed withsaturated sodium bicarbonate and then brine, filtered and concentrated.The residue was redissolved in 50% acetic acid in water (10 mL),filtered and purified by reverse phase preparative HPLC to give thetitle compound as its bis TFA salt (27 mg). (m/z): [M+H]⁺ calcd forC₂₃H₂₉N₃O, 364.24; found 364.3.

Preparation 7: Synthesis of3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamide

To a solution of the HCl salt of3-endo-[8-(2-oxo-ethyl)-8-azabicyclo[3.2.1]oct-3-yl]benzamide (554 mg,1.80 mmol) in dichloromethane (9.0 mL) at 0° C. was added sodiumtriacetoxyborohydride (496 mg, 2.34 mmol) followed by cyclohexylmethylamine (244 mg, 2.16 mmol) and N,N-diisopropylethylamine (233 mg,1.80 mmol). The ice-water cooling bath was removed after addition andthe reaction was allowed to warm to room temperature and stirred at thattemperature for one hour. The reaction mixture was then concentrated.The residue was redissolved in 50% acetic acid in water (10 mL),filtered, and purified by reverse phase preparative HPLC to give thetitle compound as its bis TFA salt (400 mg). (m/z): [M+H]⁺ calcd forC₂₃H₃₅N₃O, 370.29; found 370.5.

Preparation 8: Synthesis of cyclohexylmethyl-(2-oxo-ethyl)carbamic acidtert-butyl ester a. Preparation of 2-(cyclohexylmethylamino)ethanol

A mixture of cyclohexylmethylbromide (23.2 g, 131 mmol) and ethanolamine(47.9 g, 786 mmol) in EtOH (131 mL) was heated at 75° C. for 2 hours.NMR analysis of an aliquot showed the reaction was complete. Thereaction was then concentrated to remove ethanol and the resultingresidue was diluted with DCM. The organic layer was washed successivelywith water (3×100 mL) and brine (100 mL) and then dried over sodiumsulfate, filtered, and concentrated to give the title intermediate as alight yellowish oil (10.57 g). (m/z): [M+H]⁺ calcd for C₉H₁₉NO, 158.16;found 158.2. ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 3.59 (t, J=5.4 Hz, 2H),2.73 (t, J=5.4 Hz, 2H), 2.42 (d, J=6.6 Hz, 2H), 1.6-1.77 (m, 6H),1.36-1.6 (m, 1H), 1.10-1.28 (m, 2H), 0.82-0.95 (m, 2H).

b. Preparation of cyclohexylmethyl-(2-hydroxyethyl) carbamic acidtert-butyl ester

To the solution of the product of the previous step (10.57 g, 67.3 mmol)in DCM (200 mL) at 0° C. was added a solution ofdi-tert-butyldicarbonate (13.2 g, 60.57 mmol) in DCM (100 mL) dropwise.The resulting mixture was allowed to slowly warm to room temperatureovernight. The mixture was washed successively with 1N aq HCl (3×100mL), saturated sodium bicarbonate (100 mL) and brine (100 mL). Afterdrying over sodium sulfate, the organic layer was filtered andconcentrated to give the title compound as a light yellowish oil (16.5g). ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 3.71-3.73 (m, 2H), 3.37 (brs, 2H),3.03-3.05 (m, 2H), 1.61-1.72 (m, 6H), 1.3-1.5 (m, 1H), 1.48 (s, 9H),1.14-1.21 (m, 2H), 0.86-0.91 (m, 2H).

c. Synthesis of cyclohexylmethyl-(2-oxo-ethyl)carbamic acid tert-butylester

To the product of the previous step (16.5 g, 64.2 mmol) in DCM (256 mL)at 0° C. was added sequentially dimethylsulfoxide (7.52 g, 96.3 mmol),N,N-diisopropylethylamine (20.74 g, 160.5 mmol) and pyridine sulfurtrioxide complex (25.5 g, 160.5 mmol). Thirty minutes later, NMRanalysis of an aliquot showed the reaction was complete. The mixture wasthen washed successively with 1N aq HCl (3×100 mL), saturated sodiumbicarbonate and brine, filtered through a pad of silica gel and elutedwith DCM. After concentration, the title compound was obtained as alight yellowish oil (10.46 g). ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.55 (s,1H), 3.88 (s, 1H), 3.79 (s, 1H), 3.07-3.15 (m, 2H), 1.56-1.72 (m, 6H),1.3-1.5 (m, 1H), 1.4 (s, 9H), 1.1-1.25 (m, 2H), 0.87-0.98 (m, 2H).

Preparation 9: Synthesis of3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamidea. Preparation of{2-[3-endo-(3-carbamoylphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}cyclohexylmethyl-carbamicacid tert-butyl ester

To a stirred solution of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)benzamide(1.16 g, 5.0 mmol) prepared according to the process sequence ofPreparation 13, in DCM (20 mL) at 0° C. was added a solution ofcyclohexylmethyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester (1.53 g,6.0 mmol) in DCM (5 mL) followed by sodium triacetoxyborohydride (1.27g, 6.0 mmol). The resulting mixture was warmed to room temperature afteraddition and stirred at that temperature for 30 minutes until reactionwas determined by mass spectrometry to be complete. The mixture was thendiluted with DCM, washed twice with saturated sodium bicarbonate,followed by brine, dried over sodium sulfate, filtered and concentratedto give a yellowish oil, which was used in the next step without furtherpurification. (m/z): [M+H]⁺ calcd for C₂₈H₄₃N₃O₃ 470.34; found 470.6.

b. Synthesis of3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamide

The oily residue of the previous step was dissolved in DCM (12 mL) andtreated with TFA (12 mL) at room temperature for about 40 minutes. Thereaction was judged complete by mass spectrometry. The mixture was thenconcentrated and co-evaporated three times with ethyl acetate, dilutedwith DCM and basified to pH 8.0 with saturated sodium bicarbonate. Thelayers were separated and aqueous layer was extracted with DCM one moretime. The combined organic layer was then washed with brine, dried oversodium sulfate, filtered, and concentrated to give a brownish oil.Further drying under vacuum provided a light brownish foam (1.34 g).(m/z): [M+H]⁺ calcd for C₂₃H₃₅N₃O, 370.29; found 370.4. ¹H NMR (CDCl₃,300 MHz) δ (ppm): 7.89 (s, 1H), 7.70-7.72 (m, 1H), 7.54-7.56 (m, 1H),7.39-7.44 (m, 1H), 3.43 (brs, 2H), 3.16-3.21 (m, 1H), 3.06-3.10 (m, 2H),2.91 (d, J=7.2 Hz, 2H), 2.65-2.69 (m, 2H), 2.05-2.51 (m, 2H), 2.01-2.05(m, 2H), 1.79-1.91 (m, 8H) 1.60-1.63 (m, 2H), 1.27-1.42 (m, 3H),1.09-1.17 (m, 2H).

Preparation 10: Synthesis of(2-oxo-ethyl)-(4-trifluoromethylbenzyl)-carbamic acid tert-butyl estera. Preparation of 2-(4-trifluoromethylbenzylamino)ethanol

Following the method of Preparation 8, step a, 4-trifluoromethylbenzylbromide (664 mg, 2.78 mmol) was heated with ethanolamine (1.02 g, 16.7mmol) in ethanol (3 mL) at 75° C. overnight. The product was isolated togive the title intermediate as a yellowish oil (585 mg). (m/z): [M+H]⁺calcd for C₁₀H₁₂F₃NO, 220.10; found 220.3. ¹H NMR (CDCl₃, 300 MHz) δ(ppm): 7.59 (d, J=7.8 Hz, 2H), 7.45 (d, J=7.8 Hz, 2H), 3.88 (s, 2H),3.66-3.70 (m, 2H), 2.80-2.83 (m, 2H).

b. Preparation of (2-hydroxyethyl)-(4-trifluoromethylbenzyl)carbamicacid tert-butyl ester

Following the method of Preparation 8, step b, the product of theprevious step (585 mg, 2.65 mmol) was treated with di-tert-butyldicarbonate (525 mg, 2.41 mmol) to give the title intermediate as alight yellowish oil (796 mg). ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.57 (d,J=7.8 Hz, 2H), 7.32 (d, J=7.8 Hz, 2H), 4.52 (brs, 2H), 3.71 (brs, 2H),3.40 (brs, 2H), 1.44 (brs, 9H).

c. Synthesis of (2-oxo-ethyl)-(4-trifluoromethylbenzyl)carbamic acidtert-butyl ester

Following the method of Preparation 8, step c, the product of theprevious step (796 mg, 2.49 mmol) was oxidized with sulfur trioxidepyridine complex (990 mg, 6.22 mmol) to give the title compound as alight yellowish oil (538 mg).

Preparation 11: Synthesis of3-endo-{8-[2-(4-trifluoromethylbenzylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}phenola. Preparation of{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-(4-trifluoromethylbenzyl)carbamicacid tert-butyl ester

Following the method of Preparation 9, step a,(2-oxo-ethyl)-(4-trifluoromethyl-benzyl)carbamic acid tert-butyl ester(253 mg, 1.84 mmol) was reacted with the TFA salt of3-endo-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol, prepared by the method ofPreparation 4 (126 mg, 0.92 mmol) to give the title intermediate as ayellowish oil, which was used directly in the next step.

b. Synthesis of3-endo-{8-[2-(4-trifluoromethylbenzylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}phenol

Following the method of Preparation 9, step b, the product of theprevious step was treated with TFA (1.5 mL) and dichloromethane (1.5 mL)and purified by reverse phase preparative HPLC to give the titlecompound as its bis TFA salt (142 mg). (m/z): M+H]⁺ calcd forC₂₃H₂₇F₃N₂O, 405.22; found 405.2. ¹H NMR (CD₃OH, 300 MHz) δ (ppm): 7.75(d, J=7.8 Hz, 2H), 7.68 (d, J=7.8 Hz, 2H), 7.11-7.16 (m, 1H), 6.91-6.94(m, 1H), 6.87 (s, 1H), 6.62-6.65 (m, 1H), 4.34 (s, 2H), 4.04 (brs, 2H),3.52 (t, J=6.3 Hz, 2H), 3.31-3.39 (m, 2H), 3.13-3.20 (m, 1H, 2.52-2.59(m, 4H), 2.02-2.06 (m, 2H), 1.87-1.90 (m, 2H).

Preparation 12: Synthesis of3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-benzamide a. Preparation of8-benzyl-3-(3-methoxyphenyl)-8-azabicyclo[3.2.1]oct-2-ene

To a 500 mL flask fitted with a magnetic stir bar was added8-benzyl-3-exo-(3-methoxy-phenyl)-8-azabicyclo[3.2.1]octan-3-ol (21.44g, 66.2 mmol) followed by acetic anhydride (150 mL). Ytterbium triflate(20.51 g, 33.1 mmol) was added as a solid, and the reaction solidified.Additional acetic anhydride (100 mL) was added to suspend the solid. Thereaction was then heated to 60° C. for 4 hours. The stirring was stoppedand the reaction was diluted with ethyl acetate and quenched carefullywith 1N NaOH. The organic layer was washed with brine then dried overmagnesium sulfate. Solvent was removed in vacuo to give the titleintermediate as a sticky yellow oil (9.9 g, 48% yield). (m/z): [M+H]⁺calcd for C₂₁H₂₃NO, 306.19; found 306.3.

b. Preparation of 3-endo-(3-methoxyphenyl)-8-azabicyclo[3.2.1]octane

To a small Parr flask containing the product of the previous step (9.9g, 32.5 mmol) was added ethanol (70 mL). The mixture was stirred at roomtemperature until the reactant was fully dissolved. To the solution wasadded palladium hydroxide (4.45 g, ˜50 wt %) as a solid, portionwise,with care. The reaction vessel was purged with dry nitrogen and placedunder a hydrogen atmosphere (55 psi) overnight. When the reaction wascomplete by HPLC, the reaction was purged with nitrogen and filteredthrough Celite. The solvent was removed in vacuo to give the titleintermediate as a yellow oil (6.9 g, 98% yield). (m/z): [M+H]⁺ calcd forC₁₄H₁₉NO, 218.16; found 218.3.

c. Preparation of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-phenol

To a 1-L round bottom flask fitted with a magnetic stirbar was added theproduct of the previous step (6.9 g, 31.79 mmol) and dichloromethane(200 mL). The reaction was cooled in a dry ice/acetone bath to −78° C.for 15 minutes. To the cooled reaction was added boron tribromide as a1M solution in dichloromethane (64 mL, 63.59 mmol) quickly. The reactionwas permitted to warm slowly to room temperature over a period of 20hours. Methanol was carefully added to quench the reaction. The stir barwas removed and the solvent was removed in vacuo to give a crunchy brownsolid. The solid was dissolved in methanol. The solvent was removed invacuo to give a crunchy brown solid. The solid was dissolved again inmethanol. The solvent was removed in vacuo to give a crunchy brown solidwhich was then dried under vacuum. The dried solid was then dissolved indichloromethane and the solution was washed with 1N NaOH and saturatedsodium chloride solution. The organic layer was separated and dried overanhydrous sodium sulfate. Solvent was removed in vacuo to afford thetitle intermediate as a yellow oil. (m/z): [M+H]⁺ calcd for C₁₃H₁₇NO,204.14; found, 204.3.

d. Preparation of3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester

To a 500 mL reaction flask containing3-endo-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol (2.5 g, 12.3 mmol) wasadded dichloromethane (100 mL) under a dry nitrogen atmosphere and thentetrahydrofuran (70 mL). To the slurry was then addedN,N-diisopropylethylamine (3 mL) and di-tert-butyl dicarbonate (3 mL,12.3 mmol) in one portion as a melted liquid. The reaction was allowedto stir at room temperature over a period of 16 hours. When the reactionwas complete by HPLC, the reaction mixture was transferred to a largerflask and most of the solvent was removed. The remaining residue wasdissolved in ethyl acetate and the organic layer was washed withsaturated aqueous sodium bicarbonate and saturated aqueous sodiumchloride. The organic layer was dried over anhydrous magnesium sulfateand solvent was removed in vacuo to yield crude title intermediate. Thecrude material was chromatographed on silica gel using 20-25% ethylacetate/hexanes as the mobile phase. Fractions were combined and solventwas removed in vacuo to give 2.4 g of purified product. The purifiedmaterial was dissolved in dichloromethane (˜10 mL) and hexanes (150 mL)were added. Dichloromethane was removed by rotary evaporation. Thesolution was transferred to an Erlenmeyer flask and some seed crystalsfrom a previous preparation by the same method were added. The solutionwas left to crystallize overnight. Crystals were isolated via filtrationand washed with hexanes. Drying under vacuum gave the title intermediateas white needles (1.01 g, 27% yield). The mother liquor began to growcrystals, which were harvested, collected, washed with hexanes, anddried under vacuum to give the title intermediate as white needles (850mg, 23% yield). (m/z): [M+H]⁺ calcd for C₁₈H₂₅NO₃ 304.19; found 304.3,248.3 (parent—tert-butyl).

e. Preparation of3-endo-(3-trifluoromethanesulfonyloxy-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

To a 50 mL reaction flask fitted with a magnetic stirbar and purged withdry nitrogen was added3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester (587 mg, 1.94 mmol) and dimethylformamide (10 mL). Thereaction was stirred until a solution formed, then potassium carbonate(0.40 g, 2.90 mmol) and N-phenyltrifluoromethanesulfonimide (1.03 g,2.90 mmol) were added together as solids in one portion. The reactionwas heated to 50° C. overnight. The reaction was diluted with 1:1 ethylacetate:hexanes and water and the organic layer was washed with brineand dried over anhydrous magnesium sulfate. Solvent was removed in vacuoto give the title intermediate as a colorless oil (856 mg, >100% yield).(m/z): [M+H]⁺ calcd for C₁₉H₂₄F₃NO₅S, 436.14; found 436.2, 380.3(parent—tert-butyl).

f. Preparation of3-endo-(3-cyanophenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester

To a 1 L round bottom flask fitted with a magnetic stirbar and purgedwith dry nitrogen was added3-endo-(3-trifluoromethanesulfonyloxy-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (38.4 g, 88.3 mmol) and dimethylformamide (320mL). The solution was stirred for 5 minutes to dissolve all startingmaterial, then degassed under vacuum. A dry nitrogen atmosphere wasagain introduced. To the degassed solution was added zinc cyanide (15.5g, 132 mmol) and tetrakis(triphenylphosphine)palladium (0) (5.1 g, 4.41mmol) together as solids in one portion. The reaction was again degassedunder vacuum to remove incidental oxygen, and a dry nitrogen atmospherewas introduced. The reaction was heated to 80° C. for 4 hours. Thereaction was cooled to room temperature and diluted with isopropylacetate (500 mL). The resulting cloudy solution was filtered throughCelite (10 g). The resulting organic solution was transferred to aseparatory funnel and washed with saturated aqueous sodium bicarbonate(400 mL) and saturated aqueous sodium chloride (400 mL). The organiclayer was separated and dried over anhydrous sodium sulfate (30 g).Drying agent was removed via filtration and solvent was removed in vacuoto give crude title intermediate as waxy brown crystals (29.9 g, >100%yield). (m/z): [M+H]⁺ calcd for C₁₉H₂₄N₂O₂ 313.19; found 313.3, 257.3(parent—tert-butyl).

g. Synthesis of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-benzamide

3-endo-(3-Cyanophenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester (4.8 g, 15.36 mmol) was weighed into a 500 mL roundbottom flask and diluted with DMSO (105 mL). Potassium carbonate (3.18g, 23.04 mmol) was added as a solid followed by 30% hydrogen peroxide inwater (8 mL) carefully behind a blast shield. The reaction was stirredopen to air overnight at room temperature. When the reaction wascomplete by HPLC, water (160 mL) was added and the reaction wasextracted into ethyl acetate (3×150 mL). Combined organic layers werewashed with sodium sulfite (all aqueous layers were quenched forperoxide with sodium sulfite) and brine and dried over sodium sulfate.Solvent was removed in vacuo to give the protected intermediate3-(3-carbamoylphenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester as a colorless oil (4.8 g, 95% yield.) (m/z): [M+H]⁺calcd for C₁₉H₂₆N₂O₃ 331.20; found 331.4, 275.0 (parent—tert-butyl).

The protected intermediate is treated with dichloromethane andtrifluoroacetic acid according to the method of Preparation 4, step e toprovide the TFA salt of the title compound.

Preparation 13: Synthesis of3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-benzamide a. Preparation of8-benzyl-3-exo-(3-methoxyphenyl)-8-azabicyclo[3.2.1]octan-3-ol

To a 3 L-3-necked flask fitted with an overhead stirrer and flushed withdry nitrogen was added cerous chloride powder (88.2 g, 0.35 mol). Thesolid was diluted with anhydrous tetrahydrofuran (500 mL) and cooled to0° C. To the suspension was added 1M 3-methoxyphenyl magnesium bromidein THF (360 mL, 0.36 mol) dropwise while the temperature was maintainedbelow 10° C. The resulting solution was stirred at 0° C. for 1.5 hours.A solution of 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one (54.5 g, 0.25mol) in tetrahydrofuran (50 mL) was then added dropwise, whilemaintaining the internal temperature below 5° C. The resulting solutionwas stirred at 0° C. for 2 hours. The reaction was quenched with 10%aqueous acetic acid (400 mL) and stirred for 30 minutes at roomtemperature. Saturated sodium chloride solution (400 mL) was then addedand the resulting suspension was stirred at room temperature for 20hours to allow complete crystallization of product as the acetate salt.The crystals were filtered and washed with cold water (200 mL) followedby isopropyl acetate (200 mL) and dried under vacuum to give the titleintermediate as a white crystalline powder (91.1 g, 93% yield). (m/z):[M+H]⁺ calcd for C₂₁H₂₅NO₂ 324.20; found, 324.5.

b. Preparation of8-benzyl-3-(3-methoxyphenyl)-8-azabicyclo[3.2.1]oct-2-ene

To a 1 L flask fitted with a magnetic stir bar was added8-benzyl-3-exo-(3-methoxy-phenyl)-8-azabicyclo[3.2.1]octan-3-ol as theacetate salt (80.4 g, 0.209 mol) followed by 6M aqueous hydrochlorideacid (300 mL). The reaction was heated to 70° C. for 2 hours. Thestirring was stopped and the reaction was diluted with dichloromethane(200 mL). The mixture was transferred to a separatory funnel and thelayers were mixed, then allowed to settle. The organic layer was removedand saved. The aqueous layer was extracted with dichloromethane (2×200mL). The combined organic layers were washed with saturated aqueoussodium chloride solution (400 mL) and dried over anhydrous sodiumsulfate (30 g). Solvent was removed in vacuo to give the hydrochloridesalt of the title intermediate as a sticky yellow oil (65.4 g, 91%yield). (m/z): [M+H]⁺ calcd for C₂₁H₂₃NO, 306.19; found 306.3.

c. Preparation of 3-endo-(3-methoxyphenyl)-8-azabicyclo[3.2.1]octane

To a 1 L round-bottom flask containing of the product of the previousstep (65.4 g, 0.191 mol) was added ethanol (300 mL). The mixture wasstirred at room temperature until the intermediate was fully dissolved.To the solution was added palladium hydroxide (6.7 g, ˜10 wt %) as asolid, portionwise, with care. The reaction vessel was purged with drynitrogen and hydrogen was introduced carefully via balloon and needle.The hydrogen was bubbled through the solution for 10 minutes, and thesolution was allowed to stir overnight under a hydrogen atmosphere. Whenthe reaction was complete by HPLC, the hydrogen was removed from thereaction mixture and the vessel was purged with dry nitrogen for 10minutes. The reaction was then filtered through Celite (5 g), and theCelite cake was washed with ethanol (100 mL). The combined ethanolsolution was evaporated in vacuo, and the resulting residue wasdissolved in dichloromethane (400 mL). The organic layer was washed with3N sodium hydroxide (300 mL). The layers were separated and the aqueouslayer was extracted with dichloromethane (2×200 mL). Combined organiclayers were washed with aqueous sodium chloride (300 mL) and dried overpotassium carbonate (30 g). The drying agent was removed via filtrationand solvent was removed in vacuo to give the title intermediate as ayellow oil (27.6 g, 66% yield). (m/z): [M+H]⁺ calcd for C₁₄H₁₉NO,218.16; found 218.3.

d. Preparation of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-phenol

To a 1-L round bottom flask fitted with a magnetic stirbar and anaddition funnel was added the product of the previous step (27.6 g,0.127 mol) and dichloromethane (300 mL). The reaction was cooled in adry ice/acetone bath to −78° C. To the cooled reaction was added borontribromide (1M solution in dichloromethane, 152 mL, 0.152 mol). Thereaction was permitted to warm slowly to room temperature over a periodof 20 hours. The reaction was placed on an ice bath and methanol (100mL) was carefully added to quench the reaction. The solvent was removedin vacuo to give a crunchy beige solid. The solid was redissolved inmethanol (100 mL). The solvent was removed in vacuo to give a crunchybeige solid. The solid was redissolved again in methanol (100 mL). Thesolvent was removed in vacuo to give a crunchy beige solid which wasthen dried under vacuum for 2 hours. The dried solid was then suspendedin ethanol (110 mL) and the solution was heated on an oil bath to 80° C.To the hot solution was added just enough methanol to dissolve all thesolid material (72 mL). The solution was cooled slowly to roomtemperature, and white crystals of the hydrobromide salt of the titleintermediate were allowed to form. The solution was then further cooledto −20° C. in the freezer for one hour. The crystallization was warmedto room temperature and the crystals were collected via filtration. Thewhite crystals were washed with cold ethanol (35 mL) and dried underhouse vacuum to give the hydrobromide salt of the title intermediate asa white powder (19.5 g, 54% yield). The mother liquor was evaporated togive a crunchy beige solid. The solid was redissolved in ethanol (30 mL)and heated to 80° C. A clear brown solution formed. The solution wascooled to room temperature and then to −20° C. for one hour. Crystalswere then collected via filtration, washed with cold ethanol (10 mL),and dried under vacuum to give a second crop of crystals (5.5 g, 15%yield). (m/z): [M+H]⁺ calcd for C₁₃H₁₇NO, 204.14; found, 204.4.

e. Preparation of3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester

To a 500 mL reaction flask containing the hydrobromide salt of3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-phenol (24.8 g, 0.087 mol) wasadded dichloromethane (200 mL) under a dry nitrogen atmosphere. Theslurry was cooled to 0° C. To the slurry was then addedN,N-diisopropylethylamine (22.75 mL, 0.13 mol) and di-tert-butyldicarbonate (19.03 g, 0.087 mol) in one portion as a solid. The reactionwas allowed to warm to room temperature over a period of 16 hours. Whenthe reaction was complete by HPLC, the reaction mixture (now a clearlight brown solution) was transferred to a separatory funnel and dilutedwith isopropyl acetate (200 mL). The organic mixture was washed withsaturated aqueous sodium bicarbonate (300 mL). The organic layer wasremoved and the aqueous layer was extracted with isopropyl acetate (200mL). The combined organic layers were washed with aqueous sodiumchloride solution (300 mL), the layers were separated, and the organiclayer was dried over anhydrous sodium sulfate (20 g). Solvent wasremoved in vacuo to afford the title intermediate as a white solid (27.1g, >100% yield). (m/z): [M+H]⁺ calcd for C₁₈H₂₅NO₃ 304.19; found 304.3,248.3 (parent—tert-butyl).

f. Preparation of3-endo-(3-trifluoromethanesulfonyloxy-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

To a 500 mL reaction flask fitted with a magnetic stirbar and purgedwith dry nitrogen was added the product of the previous step (27.1 g,0.089 mol) and dichloromethane (250 mL). The solution was cooled to 0°C. on an ice bath. To the cold solution was added triethylamine (12.4mL, 0.097 mol) and trifluoromethane sulfonyl chloride (9.43 mL, 0.097mol) dropwise while maintaining the internal temperature below 10° C. Tothis reaction was added solid 4-N,N-dimethylaminopyridine (0.544 g, 4.46mmol) in one portion. The reaction was warmed to room temperature andstirred for 30 minutes. The final solution was transferred to aseparatory funnel. The organic layer was washed with saturated aqueoussodium bicarbonate (200 mL) and saturated aqueous sodium chloride (200mL). The organic layer was separated and dried over anhydrous sodiumsulfate (20 g). Drying agent was removed via filtration and solvent wasremoved in vacuo to yield the title intermediate as a clear oil (38.4 g,98% yield). (m/z): [M+H]⁺ calcd for C₁₉H₂₄F₃NO₅S, 436.14; found 436.2,380.3 (parent—tert-butyl).

g. Preparation of3-endo-(3-cyanophenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester

To a 1 L round bottom flask fitted with a magnetic stirbar and purgedwith dry nitrogen was added the product of the previous step (38.4 g,88.3 mmol) and dimethylformamide (320 mL). The solution was stirred for5 minutes to dissolve all starting material, then degassed under vacuum.A dry nitrogen atmosphere was again introduced. To the degassed solutionwas added zinc cyanide (15.5 g, 132 mmol) andtetrakis(triphenylphosphine)palladium (0) (5.1 g, 4.41 mmol) together assolids in one portion. The reaction was again degassed under vacuum anda dry nitrogen atmosphere was introduced. The reaction was heated to 80°C. for 4 hours. The reaction was cooled to room temperature and dilutedwith isopropyl acetate (500 mL). The resulting cloudy solution wasfiltered through Celite (10 g). The resulting organic solution waswashed with saturated aqueous sodium bicarbonate (400 mL) and saturatedaqueous sodium chloride (400 mL). The organic layer was separated anddried over anhydrous sodium sulfate (30 g). Drying agent was removed viafiltration and solvent was removed in vacuo to give crude titleintermediate as waxy brown crystals (29.9 g, >100% yield). (m/z): [M+H]⁺calcd for C₁₉H₂₄N₂O₂ 313.19; found 313.3, 257.3 (parent—tert-butyl).

h. Synthesis of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-benzamide

To a 15 mL round bottom flask fitted with a magnetic stirbar and areflux condenser was added3-endo-(3-cyanophenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester (500 mg, 1.60 mmol) as a solid followed bytrifluoroacetic acid (4 mL). To the solution was added concentratedsulfuric acid (440 μL, 5.0 equiv.). The reaction was heated to 65° C.for 10 hours. The reaction was poured into a solution of saturatedaqueous sodium chloride (70 mL) and transferred to a separatory funnel.The aqueous layer was washed with isopropyl acetate (50 mL) to removeresidual triphenylphosphine oxide from the previous step. To the aqueouslayer was added 3 N aqueous sodium hydroxide (15 mL) to adjust the pH to14. The aqueous layer was extracted with tetrahydrofuran (2×50 mL).Combined organic layers were dried over anhydrous sodium sulfate (3 g).Drying agent was removed via filtration and the solvent was removed invacuo to give the title compound as a crunchy, partially crystallinefoam (300 mg, 79% yield). (m/z): [M+H]⁺ calcd for C₁₄H₁₈N₂O, 231.15;found 231.2.

Preparation 14: Synthesis of methoxycarbonylmethanesulfonyl-acetic acida. Preparation of methoxycarbonylmethylsulfanyl-acetic acid tert-butylester

To a solution of mercapto-acetic acid methyl ester (1.0 g, 9.42 mmol) indimethylformamide (10 mL) at room temperature was added potassiumcarbonate (1.69 g) followed by bromo-acetic acid tert-butyl ester (1.84g, 9.42 mmol). The resulting suspension was stirred at ambienttemperature overnight and then diluted with hexanes. The organic layerwas washed with water three times and brine once, dried over sodiumsulfate, filtered and concentrated to give a colorless oil, which wasused directly in next step without purification. ¹H NMR (CDCl₃, 300 MHz)δ (ppm): 3.72 (s, 3H), 3.37 (s, 2H), 3.27 (s, 2H), 1.45 (s, 9H).

b. Preparation of methoxycarbonylmethanesulfonyl-acetic acid tert-butylester

To a solution of the product of the previous step (830 mg, 3.75 mmol) indichloromethane (25 mL) at 0° C. was added 3-chloroperoxybenzoic acid(1.94 g, 11.25 mmol). The resulting mixture was allowed to warm to roomtemperature after addition and stirred at ambient temperature for 2.5hours. The reaction was quenched with saturated sodium sulfite (30 mL)and the mixture was stirred at ambient temperature for 15 minutes. Thelayers were separated and the organic layer was washed sequentially with1N aqueous NaOH, saturated sodium bicarbonate, and brine. The organiclayer was dried over sodium sulfate, filtered, and concentrated to givethe title intermediate as a colorless oil (683 mg), which was useddirectly in the next step. ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 4.32 (s,2H), 4.21 (s, 2H), 3.81 (s, 3H), 1.48 (s, 9H).

c. Synthesis of methoxycarbonylmethanesulfonyl-acetic acid

The product of the previous step (683 mg) was treated withtrifluoroacetic acid (10 mL) at ambient temperature for two hours. Themixture was concentrated, redissolved in ethyl acetate and the organiclayer was washed with water followed by brine. The organic layer wasdried over sodium sulfate, filtered, and concentrated to give titlecompound as a colorless oil which turned into a wax upon drying undervacuum. (345 mg). ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 4.39 (s, 2H), 4.33(s, 2H), 3.83 (s, 3H).

Preparation 15: Synthesis of(S)-2,2-dimethyl-[1,3]dioxolane-4-carboxylic acid

To a solution of α,β-isopropylidene-1-glyceric acid methyl ester (2.2 g,13.7 mmol) in MeOH (20 mL) at ambient temperature was added lithiumhydroxide monohydrate (1.15 g, 27.4 mmol) in water (5.0 mL). Theresulting mixture was stirred at ambient temperature overnight. Afterconcentration, the residue was acidified with 10% aqueous HCl (20 mL)and then extracted with dichloromethane three times. The combinedorganic layer was washed with brine twice, dried over sodium sulfate,filtered and concentrated to give the title compound as a colorless oil(819 mg). ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 4.60 (dd, J=4.5, 7.2 Hz, 1H),4.28 (dd, J=7.2, 8.7 Hz, 1H), 4.18 (dd, J=4.5, 8.7 Hz, 1H), 1.51 (s,3H), 1.40 (s, 3H).

Preparation 16: Synthesis of acetic acid[benzyl-(2-oxo-ethyl)carbamoyl]-methyl ester a. Synthesis of acetic acid[benzyl-(2-hydroxyethyl)carbamoyl]methyl ester

Benzylethanolamine (1.78 g, 11.8 mmol) was weighed into a 25 mL roundbottom flask and diluted with dichloromethane. N,N-Diisopropylethylamine(2.66 mL, 15.3 mmol) was added quickly via syringe and the reaction wascooled to 0° C. After stirring at 0° C. for 10 minutes, acetoxyacetylchloride (1.26 mL, 11.8 mmol) was added dropwise via syringe. Thereaction was stirred overnight and allowed to warm to room temperature.The reaction mixture was diluted with ethyl acetate and washed withsaturated aqueous sodium bicarbonate and saturated aqueous sodiumchloride. The organic layer was separated and dried over anhydrousmagnesium sulfate. The drying agent was removed via filtration andsolvent was removed in vacuo to give crude title intermediate as ayellow oil. The crude material was chromatographed on silica gel usingethyl acetate as the mobile phase. Fractions were combined and solventwas removed in vacuo to give pure title intermediate as a clear oil(1.75 g, 59% yield). (m/z): [M+H]⁺ calcd for C₁₃H₁₇NO₄ 252.13; found252.3.

b. Synthesis of acetic acid [benzyl-(2-oxo-ethyl)carbamoyl]methyl ester

Acetic acid [benzyl-(2-hydroxyethyl)carbamoyl]methyl ester (1.28 g, 5.10mmol) was weighed into a 200 mL round bottom flask and purged withnitrogen. Dichloromethane (50 mL) was added, and the reaction was cooledto −15° C. for 10 minutes. Dimethylsulfoxide (3.61 mL, 51.0 mmol),N,N-diisopropylethylamine (4.43 mL, 25.5 mmol), and pyridine.sulfurtrioxide complex (4.06 g, 25.5 mmol) were then added sequentially at−15° C. The reaction was allowed to warm slowly to room temperature andstirred overnight. The reaction was complete by thin layerchromatography, and was diluted with ethyl acetate. The organic solutionwas washed with saturated aqueous sodium bicarbonate and saturatedaqueous sodium chloride. The organic layer was separated and dried overanhydrous magnesium sulfate. The drying agent was removed via filtrationand solvent was removed in vacuo to give crude title compound as ayellow oil. The crude material was chromatographed on silica gel using1:1 ethyl acetate:dichloromethane as the mobile phase. Fractions werecombined and solvent was removed in vacuo to give pure title compound asa colorless oil (0.72 g, 57% yield). (m/z): [M+H]⁺ calcd for C₁₃H₁₅NO₄250.11; found 250.0.

Preparation 17: Synthesis of3-endo-[8-(2-phenethylaminoethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]benzamidea. Preparation of 2-phenethylaminoethanol

A mixture of 2-bromoethyl benzene (2.0 g, 10.8 mmol) and ethanolamine(3.96 g, 64.8 mmol) in ethanol (11 mL) was heated at 75° C. for 16.5hours at which time LC/MS showed the reaction was complete. The reactionmixture was then concentrated to remove ethanol and the resultingresidue was diluted with DCM (100 mL). The organic layer was partitionedwith water (100 mL) and the aqueous layer was extracted with DCM (50mL). The combined organic layers were washed with water (2×5 mL), driedover sodium sulfate, filtered, and concentrated to give the titleintermediate as a light yellowish oil (1.5 g). (m/z): [M+H]⁺ calcd forC₁₀H₁₅NO, 166.13; found, 166.2)¹H NMR (d₆-DMSO, 300 MHz) δ (ppm):7.13-7.29 (m, 5H), 4.4 (br, 1H), 3.42 (t, J=5.7 Hz, 2H), 2.61-2.76 (m,4H), 2.55-2.59 (t, J=5.7 Hz, 2H), 1.55 (br, 1H).

b. Preparation of (2-hydroxyethyl)phenethylcarbamic acid tert-butylester

Following the procedure of Preparation 8 step b, the product of theprevious step (1.5 g, 9.09 mmol) was reacted with di-tert-butyldicarbonate (1.78 g, 8.2 mmol) in DCM (14 mL) to provide the titleintermediate (2.26 g) as a light yellowish oil.

c. Preparation of (2-oxo-ethyl)phenethylcarbamic acid tert-butyl ester

Following the procedure of Preparation 8, step c, the product of theprevious step (2.26 g, 8.5 mmol) was converted to the titleintermediate, which was obtained as a yellowish oil (1.27 g)¹H NMR(d₆-DMSO, 300 MHz) δ (ppm): 9.37 (s, 1H), 7.21-7.28 (m, 2H), 7.17-7.20(m, 3H), 3.93 (s, 2H), 3.41 (t, 2H), 2.74 (t, 2H), 1.30 (s, 9H).

d. Preparation of{2-[3-endo-(3-carbamoylphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}phenethylcarbamicacid tert-butyl ester

Following the procedure of Preparation 9 step a,3-endo-(8-azabicyclo[3.2.1]oct-3-yl)benzamide (60 mg, 0.28 mmol),prepared by the method of Preparation 13, was reacted with(2-oxo-ethyl)phenethylcarbamic acid tert-butyl ester (87 mg, 0.34 mmol)to provide the title intermediate as a yellowish oil. (m/z): [M+H]⁺calcd for C₂₉H₃₉N₃O₃ 478.30; found, 478.4.

e. Preparation of3-endo-[8-(2-phenethylaminoethyl)-8-azabicyclo[3.2.1]oct-3-yl]-benzamide

Following the procedure of Preparation 9, step b, the product of theprevious step was treated with TFA to provide the title intermediate asa dark oil. (m/z): [M+H]⁺ calcd for C₂₄H₃₁N₃O, 378.25; found, 378.2.

Preparation 18: Synthesis of3-endo-[8-(2-(3-phenylpropylamino)ethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]benzamide

Following the procedure of Preparation 17 substituting1-bromo-3-phenylpropane for 2-bromoethyl benzene, the followingintermediates were prepared:

a. 2-(3-phenylpropylamino)ethanol ¹H NMR (d₆-DMSO, 300 MHz) δ (ppm):7.14-7.28 (m, 5H), 4.4 (br, 1H), 3.42 (t, J=5.7 Hz, 2H), 2.46-2.58 (m,6H), 1.61-1.71 (p, 2H), 1.65 (br, 1H).

b. (2-hydroxyethyl)-(3-phenylpropyl)carbamic acid tert-butyl ester

c. (2-oxo-ethyl)-(3-phenylpropyl)carbamic acid tert-butyl ester ¹H NMR(d₆-DMSO, 300 MHz) δ (ppm): 9.44 (s, 1H), 7.24-7.39 (m, 2H), 7.15-7.19(m, 3H), 3.97 (s, 2H), 3.24 (t, 2H), 2.49 (t, 2H), 1.69-1.74 (m, 2H),1.34 (s, 9H).

d.{2-[3-endo-(3-carbamoylphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-(3-phenylpropyl)carbamicacid tert-butyl ester (m/z): [M+H]⁺ calcd for C₃₀H₄₁N₃O₃ 492.31. found,492.4.

e.3-endo-{8-[2-(3-phenylpropylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-benzamide(m/z): [M+H]⁺ calcd for C₂₅H₃₃N₃O, 392.26; found, 392.4.

Preparation 19: Synthesis of3-endo-{8-(2-(2-cyclohexylethylamino)ethyl)-8-azabicyclo[3.2.1]oct-3-yl]benzamide

Following the procedure of Preparation 17 substituting1-bromo-2-cyclohexylethane for 2-bromoethyl benzene, the followingintermediates were prepared:

a. 2-(2-cyclohexylethylamino)ethanol ¹H NMR (d₆-DMSO, 300 MHz) δ (ppm):4.4 (br, 1H), 3.38-3.42 (t, J=5.7 Hz, 2H), 2.46-2.54 (m, 4H), 1.58-1.65(m, 5H), 1.06-1.29 (m, 6H), 0.82-0.89 (m, 2H).

b. (2-cyclohexylethyl)-(2-hydroxyethyl)carbamic acid tert-butyl ester

c. (2-cyclohexylethyl)-(2-oxo-ethyl)carbamic acid tert-butyl ester ¹HNMR (d₆-DMSO, 300 MHz) δ (ppm): 9.43 (s, 1H), 3.93 (s, 2H), 3.20 (t,2H), 1.64-1.68 (m, 4H), 1.38 (s, 9H), 1.30-1.37 (m, 4H), 1.14-1.27 (m,3H), 0.83-0.87 (m, 2H).

d.{2-[3-endo-(3-carbamoylphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}-(2-cyclohexylethyl)carbamicacid tert-butyl ester (m/z): [M+H]⁺ calcd for C₂₉H₄₅N₃O₃ 484.35; found,484.4.

e.3-endo-{8-[2-(2-cyclohexylethylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-benzamide(m/z): [M+H]⁺ calcd for C₂₄H₃₇N₃O, 384.29; found, 384.4.

Preparation 20: Synthesis of3-endo-{8-(2-(3-cyclohexylpropylamino)ethyl)-8-azabicyclo[3.2.1]oct-3-yl]benzamidea. Preparation of 3-cyclohexylpropionaldehyde

3-Cyclohexyl-1-propanol (3.96 g, 27.8 mmol) was dissolved in DCM (90 mL)at 0° C. and treated sequentially with dimethyl sulfoxide (3.25 g, 41.7mmol), N,N-diisopropylethylamine (8.98 g, 69.6 mmol) and sulfur trioxidepyridine complex (11 g, 69.6 mmol). After one hour, the reaction mixturewas diluted with DCM (100 mL) and washed with 1N aqueous HCl (3×50 mL),saturated sodium bicarbonate (3×50 mL), and brine. The organic layer wasdried over MgSO₄, filtered, and concentrated to yield the titleintermediate as a light yellow oil (3.8 g). ¹H NMR (d₆-DMSO, 300 MHz) δ(ppm): 9.72 (s, 1H), 3.65-3.72 (m, 2H), 2.46 (t, 2H), 1.65-1.73 (m, 3H),1.51-1.56 (m, 2H), 1.14-1.48 (m, 4H), 0.85-0.96 (m, 2H).

b. Preparation of 2-(3-cyclohexylpropylamino)ethanol

To a solution of ethanolamine (0.44 g, 7.1 mmol) in DCM (15 mL) at 0° C.was added a solution of 3-cyclohexylpropionaldehyde (1.0 g, 7.1 mmol) inDCM (10 mL) followed by sodium triacetoxyborohydride (1.67 g, 7.86mmol). The resulting mixture was warmed to room temperature. After 2.5hours the desired product was observed by mass spectrometric analysis.The reaction mixture was stirred overnight, then diluted with DCM (50mL), washed with saturated sodium bicarbonate (2×50 mL), and brine (50mL), dried over sodium sulfate, filtered, and concentrated to give aclear oil (1.0 g) which was used in the next step without furtherpurification. ((m/z): [M+H]⁺ calcd for C₁₁H₂₃NO, 186.20; found, 186.0).

Following the procedure of Preparation 17 steps b to e, substituting2-(3-cyclohexylpropylamino)ethanol for 2-phenethylaminoethanol ofPreparation 17 step b, the following intermediates were prepared:

c. (3-cyclohexylpropyl)-(2-hydroxyethyl)carbamic acid tert-butyl ester

d. (3-cyclohexylpropyl)-(2-oxo-ethyl)carbamic acid tert-butyl ester ¹HNMR (d₆-DMSO, 300 MHz) δ (ppm): 9.43 (s, 1H), 3.94 (s, 2H), 3.14 (t,2H), 1.621 (m, 4H), 1.41-1.46 (m, 5H), 1.38 (s, 9H), 1.34-1.36 (m, 4H),0.86-0.88 (m, 2H).

e.{2-[3-endo-(3-carbamoylphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}-(3-cyclohexylpropyl)carbamicacid tert-butyl ester (m/z): [M+H]⁺ calcd for C₃₀H₄₇N₃O₃ 498.36; found,498.6.

f.3-endo-{8-[2-(3-cyclohexylpropylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-benzamide(m/z): [M+H]⁺ calcd for C₂₅H₃₉N₃O, 398.31; found, 398.4.

Preparation 21: Synthesis of3-endo-(8-{2-[(4,4-difluorocyclohexylmethyl)-amino]ethyl}8-azabicyclo[3.2.1]oct-3-yl)benzamidea. Preparation of (4,4-difluorocyclohexylmethyl)carbamic acid tert-butylester

To a solution of 4-oxocyclohexylmethyl)carbamic acid tert-butyl ester(2.0 g, 8.81 mmol) in dichloromethane (50 mL) at 0° C. under nitrogenwas added bis-(2-methoxyethyl) aminosulfur trifluoride (Deoxo-Fluor®)(3.90 g, 17.62 mmol) dropwise. The reaction was allowed to warm to roomtemperature after addition and stirred at that temperature overnight.The reaction was then slowly quenched with saturated sodium bicarbonate.Additional dichloromethane (300 mL) was added and the resulting mixturewas filtered through a pad of Celite. The layers of filtrate wereseparated and the organic layer was washed with saturated sodiumbicarbonate three times followed by brine. The residue was dried oversodium sulfate, filtered and concentrated to give a brownish oil whichwas further purified by flash chromatography. The compound was elutedwith 25% (400 mL) to 30% (200 mL) and 40% (200 mL) ethylacetate/hexanes. Desired fractions were combined and concentrated togive yellowish oil which solidified upon drying under vacuum. (694 mg).

b. Preparation of (4,4-difluorocyclohexyl)methylamine

The product of the previous step (694 mg) was treated with a 1:1 mixtureof dichloromethane and trifluoroacetic acid (6 mL) at room temperaturefor thirty minutes. The reaction mixture was concentrated andco-evaporated with ethyl acetate three times. The resulting residue wasdried under vacuum to give the TFA salt of the title intermediate as abrownish oil.

c. Synthesis of3-endo-(8-{2-[(4,4-difluorocyclohexylmethyl)-amino]ethyl}8-azabicyclo[3.2.1]oct-3-yl)benzamide

To a solution of3-endo-[8-(2-oxo-ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-benzamide (185 mg,0.6 mmol) in dichloromethane (3 mL) at room temperature was added sodiumtriacetoxyborohydride (165 mg, 1.8 mmol) followed by the TFA salt of(4,4-difluorocyclohexyl)methylamine (315 mg, 1.2 mmol) indichloromethane (2 mL). The reaction mixture was stirred at roomtemperature for about one and an half hours and then concentrated. Theresulting residue was dissolved in 50% acetic acid in water (10 mL),filtered, and purified by reverse phase preparative HPLC to give the bisTFA salt of the title compound (73 mg). (m/z): [M+H]⁺ calcd forC₂₃H₃₃F₂N₃O, 406.27; found, 406.2.

Preparation 22: Synthesis of3-endo-[8-(2-benzylamino-propyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-phenol a.Preparation ofN-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-1-methyl-2-oxo-ethyl}benzamide

2-Benzoylamino-propionic acid (319 mg, 1.65 mmol) andbenzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP) (731 mg, 1.65 mmol) were added to a stirred solution of the TFAsalt of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)phenol (prepared by themethod of Preparation 4) (524 mg, 1.65 mmol) andN,N-diisopropylethylamine (0.86 mL, 4.96 mmol) in THF (14 mL) at roomtemperature, under an atmosphere of nitrogen. After 90 min, the reactionwas quenched by the addition of water (1 mL) and diluted with ethylacetate (60 mL) and washed with 1M HCl (20 mL), saturated aqueous sodiumbicarbonate (20 mL), brine (20 mL), water (20 mL) and brine (20 mL). Theorganic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by flash chromatography(EtOAc:hexanes 7:3 to 4:1) to afford the title intermediate (597 mg) asa white solid.

b. Synthesis of3-endo-[8-(2-benzylamino-propyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-phenol

Borane dimethylsulfide complex, 10-10.2M (2.16 mL, 21.6 mmol) was addeddropwise to a stirred solution of the product of the previous step (544mg, 1.44 mmol) in THF (15 mL) at −20° C., under an atmosphere ofnitrogen. Upon addition the reaction mixture was warmed to reflux. After3 hours, the reaction mixture was cooled to −20° C. and methanol (30 mL)was carefully added and stirred overnight. The reaction mixture wasconcentrated in vacuo and then diluted with 4M HCl in dioxane (10 mL)and stirred for 2 hours. The reaction mixture was again concentrated invacuo and then diluted with methanol and potassium hydroxide (10 eq) wasadded. After 2 hours, the reaction mixture was concentrated in vacuo,diluted with water (10 mL) and extracted with a mixture ofdichloromethane:THF 3:1 (2×20 mL). The organic layers were combined,dried over magnesium sulfate, filtered and concentrated in vacuo toafford the title compound (509 mg) as a white solid which was usedwithout further purification. (m/z): [M+H]⁺ calcd for C₂₃H₃₀N₂O, 351.25;found, 351.5.

Preparation 23: Synthesis ofN-[3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-phenyl]-methanesulfonamide a.Preparation of3-endo-(3-aminophenyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester

To a solution of3-endo-(3-trifluoromethanesulfonyloxy-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (400 mg, 0.92 mmol), prepared by the method ofPreparation 13, in tetrahydrofuran (9.0 mL) was added benzophenone imine(216.7 mg, 1.2 mmol), potassium tert-butoxide (154.8 mg, 1.38 mmol) andrac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (BINAP) (51.5 mg, 0.08mmol). The resulting mixture was degassed and flushed with nitrogenbefore palladium (II) acetate (19.3 mg, 0.08 mmol) was added. Themixture was then heated to 78° C. for two hours. After being cooled toroom temperature, the reaction mixture was treated with 2 N HCl (5.0 mL)for three hours and then basified to pH 8 with 5% aqueous sodiumhydroxide. The aqueous layer was extracted with ethyl acetate. Theresulting organic layer was washed with saturated sodium bicarbonate andbrine, dried over sodium sulfate, filtered, concentrated, and furtherpurified by reverse phase preparative HPLC to provide the TFA salt ofthe title intermediate. (m/z): [M+H]⁺ calcd for C₁₈H₂₆N₂O₂: 303.41;found: 303.2.

b. Preparation of3-endo-(3-methanesulfonylamino-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

To a stirred mixture of the TFA salt of3-endo-(3-aminophenyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester (114 mg, 0.37 mmol), N,N-diisopropylethylamine (146 mg,1.13 mmol) and 4-dimethylaminopyridine (DMAP) (9 mg, 0.075 mmol) in DCM(2.0 mL) at 0° C. was added a solution of methanesulfonylchloride (45mg, 0.39 mmol) in DCM (0.2 mL). Thirty minutes later, analytical HPLCindicated the reaction was not complete. Additional methanesulfonylchloride (17 mg, 0.15 mmol) was added and the mixture was stirred at 0°C. for another thirty minutes before it was quenched with saturatedsodium bicarbonate. The aqueous layer was extracted with DCM. Theorganic layer was washed with brine, dried over sodium sulfate, filteredand concentrated to give the title intermediate as a yellowish oil (140mg).

c. Synthesis ofN-[3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-phenyl]-methanesulfonamide

The oily product of the previous step was treated with DCM (2 mL) andTFA (20 mL) at room temperature for thirty minutes at which timeanalytical HPLC showed the reaction was complete. The reaction mixturewas concentrated and the resulting residue was coevaporated with ethylacetate three times and further dried under vacuum to give the TFA saltof the title intermediate as a yellowish oil, which was used withoutfurther purification.

Preparation 24: Synthesis of N-cyclohexylmethyl-(2-oxoethyl)-carbamicacid benzyl ester bisulfite adduct a. Preparation ofN-cyclohexylmethyl-(2,2-diethoxyethyl)amine

To a mixture of 2,2-diethoxyethylamine (209 mL, 1.43 mol) and MeTHF(1050 L) was added cyclohexanecarbaldehyde (107 mL, 0.89 mol). Thereaction mixture was stirred for 30 min at room temperature and cooledto 0° C. Sodium triacetoxyborohydride (378 g, 1.79 mol) was added over40 min and the reaction mixture was stirred for 2 h and cooled to 0° C.1 M NaOH (1 L) was added. The organic layer was washed with brine inwater (1:1, 2×1 L) and the volume was reduced to ˜20%. MeTHF (1 L) wasadded and the volume reduced to ˜20%. The solution of the crude titleintermediate was used directly in the next step.

b. Preparation of N-cyclohexylmethyl-(2,2-diethoxyethyl)carbamic acidbenzyl ester

To the product of the previous step (˜213 g, ˜0.9 mol) was added MeTHF(2 L) and DIPEA (233 mL, 1.34 mol). The reaction mixture was cooled to0° C. and benzylchloroformate (140 mL, 0.98 mol) was added dropwise. Thereaction mixture was stirred for 30 min at 0° C., for 2 h at 0° C. toroom temperature, and then for 1 h at room temperature. Water (1.6 L)was added and the reaction mixture was stirred for 10 min. The phaseswere separated and the organic layer was washed with sodium bicarbonate(1.6 L) and water (1.6 L). The layers were separated and the organiclayer was reduced to about 20%. MeTHF (1 L) was added and the volumereduced to ˜20%. The solution of the crude title intermediate was useddirectly in the next step.

c. Synthesis of N-cyclohexylmethyl-(2-oxoethyl)-carbamic acid benzylester bisulfite adduct

To the product of the previous step (˜302 g, ˜0.62 mol) and acetonitrile(2 L) was added 1 M HCl (2 L) and the reaction mixture was stirred at30° C. for 7 h. Ethyl acetate (2 L) was added and the reaction mixturewas stirred for 10 min. The phases were separated, the organic layer waswashed with 1 M HCl (1.5 L), the phases were again separated and theorganic layer was washed with 0.5 M HCl (1 L). Sodium bisulfite (71.4 g,0.69 mol) was added and the reaction mixture was stirred overnight, andthen filtered. The reactor and filter cake were washed with ethylacetate (1 L). The resulting solution was dried in air for 2 h and undervacuum overnight to provide the title compound as white solid (199g, >99% area purity by HPLC). The filtrate was treated by the sameprocedure to provide a second lot of the title compound (30 g).

Preparation 25: Synthesis of3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-benzamide a. Preparation of8-benzyl-3-(3-methoxyphenyl)-8-azabicyclo[3.2.1]oct-2-ene

To a 3 L flask was added8-benzyl-3-exo-(3-methoxyphenyl)-8-azabicyclo[3.2.1]octan-3-olhydrochloride (383.9 g, 1.06 mol), 6 M HCl (800 mL), and MeTHF (200 mL).The resulting slurry was heated at 70° C. for 2.5 h under nitrogen. Thereaction mixture was transferred to a 12 L reactor and cooled to 10° C.The reaction flask was washed with MeTHF (1 L) that was added to the 12L reactor. NaOH (50 wt % in water, 200 mL) was added and additional NaOH(50 wt %, 150 mL) was added in portions until pH ˜13 was reached. Thephases were separated, the water layer was extracted with MeTHF (1 L),and combined MeTHF layers were washed with brine (1 L). Solvent wasreduced by rotary evaporation at 30 to 40° C. yielding the titleintermediate (360 g) as a thick oil. EtOH (1.5 L) was added and thevolume was reduced to ˜500 mL and then adjusted to 1.8 L.

b. Preparation of 3-endo-(3-methoxyphenyl)-8-azabicyclo[3.2.1]octane

To 8-benzyl-3-(3-methoxyphenyl)-8-azabicyclo[3.2.1]oct-2-ene (in EtOH95%, 400 mL, 0.20 mol), prepared in the previous step, was added 6 M HCl(45 mL) and then MeTHF (50 mL). The reaction mixture was purged withnitrogen, heated to 40° C. and palladium on carbon (10 weight %, 8 g)was added. The reactor was pressurized with hydrogen (3×20 psi) and thenhydrogenated at 20 psi at 40° C. for 18 h. The reaction mixture wasfiltered through Celite, concentrated, washed with MeTHF (2×100 mL),filtered through a coarse glass filter, washed with MeTHF (10 mL) anddried on the filter to provide the HCl salt of the title intermediate aswhite solid (31 g, single isomer, (exo isomer undetectable by HPLC)). Anadditional 5.2 g of product was recovered from the mother liquor.

c. Preparation of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-phenol

To a 500 mL flask was added3-endo-(3-methoxyphenyl)-8-azabicyclo[3.2.1]octane hydrochloride (115 g,0.45 mol) and hydrobromic acid (48 weight % in water, 100 mL, 0.88 mol).The mixture was heated to 120° C. and held at that temperature for 24 hwith stirring. Additional hydrobromic acid solution (25 mL) was addedand the reaction mixture was heated with stirring for 6 h and thencooled to 70° C. Acetonitrile (200 mL) was added and the resultingslurry was cooled to 10° C. and then filtered, and the filter cake waswashed with acetonitrile (50 mL) to yield the HBr salt of the titleintermediate (99 g, >99% pure) as a white granular solid.

d. Preparation of2,2,2-trifluoro-1-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethanone

To a solution of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-phenolhydrobromide (54.4 g, 0.19 mol), toluene (210 mL), and triethylamine (40mL, 0.29 mol), was added trifluoroacetic anhydride (54 mL, 0.38 mol)over 20 min. The reaction mixture was stirred at 40° C. for 2 h. Ethylacetate (370 mL) and brine in water (1:1, 265 mL) were added. Thereaction mixture was stirred for 15 min, the phases were separated. Tothe organic layer was added saturated sodium bicarbonate (300 mL) andthe mixture was stirred vigorously overnight. The phases were separatedand the organic layer was washed with brine in water (1:1, 265 mL) driedover sodium sulfate and most of the solvent was removed by rotaryevaporation. Toluene (100 mL) was added and the solvent removed byrotary evaporation to provide the crude title intermediate.

e. Preparation of trifluoromethanesulfonic acid3-endo-[8-(2,2,2-trifluoro-acetyl)-8-azabicyclo[3.2.1]oct-3-yl]phenylester

To a 500 mL flask was added the ethyl acetate solution (220 mL) of theintermediate of the previous step (32.8 g, 0.11 mol) and triethylamine(23 mL. 0.17 mol). The solution was cooled to 5° C. and trifluoromethanesulfonyl chloride (14 mL, 0.13 mol) was added dropwise. The mixture wasallowed to warm to 25° C. and stirred at that temperature for 1 h.Saturated sodium bicarbonate (200 mL) was added, the layers wereseparated, brine (150 mL) was added to the organic layer, the layerswere again separated, and solvent was removed from the organic layer toprovide the crude title intermediate.

f. Preparation of3-endo-[8-(2,2,2-trifluoroacetyl)-8-azabicyclo[3.2.1]oct-3-yl]-benzonitrile

To a 100 mL flask was added trifluoromethanesulfonic acid3-endo-[8-(2,2,2-trifluoro-acetyl)-8-azabicyclo[3.2.1]oct-3-yl]phenylester (25.3 g, 58.7 mmol), tris(dibenzylideneacetone) dipalladium (0)(0.81 g, 0.9 mmol), 1,1′-bis(diphenylphosphino) ferrocene (1.01 g, 1.8mmol), and zinc cyanide (4.2 g, 35.8 mmol). Three times, the flask waspurged with nitrogen for 5 min and then placed under house vacuum for 5min. To the flask was added DMF (150 mL) and distilled water (2.5 mL).The solution was purged with nitrogen with stirring for 10 min, heatedto 120° C. and stirred at 120° C. under nitrogen for 4 h. When thereaction was completed 20 g of product from a previous lot, prepared bythe same procedure, was added and stirred for 20 min.

Most of the solvent was removed by distillation and the solution wascooled to 22° C. To the solution was added ethyl acetate (445 mL) andthe resulting solution was filtered through Celite. Sodium bicarbonate(450 mL) was added and the solution was stirred for 15 min. The layerswere separated and the organic layer was washed with diluted brine (2×95mL), and filtered through sodium sulfate. The volume was reduced toabout 50 mL by removal of ethyl acetate. Isopropyl alcohol (150 mL) wasadded and the solution was agitated at 22° C. for 1 h. Solids wereisolated by filtration and washed with isopropyl alcohol (2×25 mL) toprovide the title intermediate (33.5 g, 100% pure by HPLC) as anoff-white/light brown solid. A second crop of product (6.3 g, >98% pureby HPLC) was isolated from the filtrate.

g. Synthesis of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-benzamide

A solution of3-endo-[8-(2,2,2-trifluoroacetyl)-8-azabicyclo[3.2.1]oct-3-yl]-benzonitrile(10 g, 32 mmol) in sulfuric acid (96%, 12 mL) was heated to 50° C. withstirring and held at that temperature with stirring for 2 h. Thereaction mixture was cooled to 22° C. and added slowly to a 500 mL flaskcontaining 5 N NaOH (90 mL) and methanol (100 mL) which was cooled to10° C. Salt precipitates were filtered and the filtrate was stirred at22° C. for 1 h. The reaction mixture was concentrated under reducedpressure. To the residue was added MeTHF (150 mL) and the reactionmixture was stirred at 22° C. for 5 min. The layers were separated andMeTHF (100 mL) was added to the aqueous layer. The layers were separatedand brine (150 mL) was added to the combined organic layers. The layerswere separated and the organic layer was dried over potassium carbonateand filtered, and the solvent was removed. A mixture of EtOH (25 mL) andconcentrated HCl (2.6 mL) was added to the residue with stirring andthen MTBE (25 mL) was added and the solution was stirred at 22° C.Precipitated solids were filtered and air dried to provide the HCl saltof the title compound (8 g, 97% purity by HPLC) as a white solid.

Example 1: Synthesis ofN-benzyl-2-hydroxy-N-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}acetamide

3-endo-[8-(2-Benzylaminoethyl)-8-azabicyclo[3.2.1]oct-3-yl]phenol,prepared by the methods of Preparations 1 and 2 (246 mg, 0.73 mmol) wasdissolved in dichloromethane (3.6 mL) and N,N-diisopropylethylamine (123mg, 0.95 mmol) at room temperature. The resulting mixture was cooled to0° C. Acetoxyacetyl chloride (119 mg, 0.87 mmol) was added and themixture was stirred at 0° C. for about 30 minutes. The reaction wasquenched with saturated sodium bicarbonate and extracted withdichloromethane. The organic layer was washed with brine, dried oversodium sulfate, filtered and concentrated to give a yellowish oil. Theoily mixture was then dissolved in 50% acetic acid/water (10 mL),filtered and purified by preparative HPLC to give TFA salts of amono-acylated product (62 mg) and a bisacylated byproduct (160.9 mg).The bis acylated byproduct TFA salt (160.9 mg) was dissolved in ethanol(2 mL) at room temperature and treated with 1N aqueous sodium hydroxide(1.0 mL) for about 30 minutes. After concentration, the residue wasdissolved in 50% acetic acid in water (10 mL), filtered and purified byreverse phase preparative HPLC to give the TFA salt of the titlecompound as a white solid (46.5 mg). (m/z): [M+H]⁺ calcd for C₂₄H₃₀N₂O₃395.24; found, 395.3.

Example 2: Synthesis ofN-benzyl-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}acetamide

To a solution of the TFA salt of3-endo-[8-(2-benzylaminoethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]phenol,prepared by the methods of Preparations 1 and 2 (25 mg, 0.044 mmol) indichloromethane (0.2 mL) at room temperature was addedN,N-diisopropylethylamine (23 mg, 0.177 mmol), followed byacetylchloride (0.044 mmol). After about 10 minutes, the reactionmixture was concentrated. The residue was redissolved in 50% aceticacid/water (1.5 mL), filtered, purified by reverse phase preparativeHPLC to provide the TFA salt of the title compound (10 mg). (m/z):[M+H]⁺ calcd for C₂₄H₃₀N₂O₂ 379.23; found, 379.2.

Examples 3-5

Using processes similar to that of Example 2, except replacing theacetylchloride with 0.044 mmol of the appropriate acyl chloride, the TFAsalts of the compounds of Examples 3-5 were prepared.

Example 3

cyclopentanecarboxylic acidbenzyl-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-amide(18.3 mg) (m/z): [M+H]⁺ calcd for C₂₈H₃₆N₂O₂, 433.29; found 433.2.

Example 4

N-benzyl-2-ethyl-N-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}butyramide(15.1 mg) (m/z): [M+H]⁺ calcd for C₂₈H₃₈N₂O₂, 435.30. found 435.2.

Example 5

N-benzyl-N-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}succinamicacid methyl ester (19.6 mg) (m/z): [M+H]⁺ calcd for C₂₇H₃₄N₂O₂, 451.26;found 451.2.

Example 6: Synthesis ofN-benzyl-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}succinamicacid

To a solution of the TFA salt of3-endo-[8-(2-benzylaminoethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]phenol,prepared by the methods of Preparations 1 and 2 (110 mg, 0.195 mmol) indichloromethane (1.0 mL) at room temperature was addedN,N-diisopropylethylamine (101 mg, 0.78 mmol) followed by3-carbomethoxypropionyl chloride (44 mg, 0.29 mmol). After about thirtyminutes, the reaction mixture was concentrated. The residue wasredissolved in ethanol (2 mL), treated with lithium hydroxidemonohydrate (33 mg, 0.78 mmol) in water (1 mL) for about thirty minutes,and then concentrated. The residue was redissolved in 50% acetic acid inwater (10 mL), filtered and purified by reverse phase preparative HPLCto give the TFA salt of the title compound (46.5 mg). (m/z): [M+H]⁺calcd for C₂₆H₃₂N₂O₂, 437.25; found 437.12.

Example 7: Synthesis ofN-cyclohexylmethyl-N-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}acetamide

To a solution of the TFA salt of3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl-phenolprepared by the method of Preparations 1 and 3 (25 mg, 0.044 mmol) indichloromethane (0.2 mL) at room temperature was addedN,N-diisopropylethylamine (34 mg, 0.26 mmol) followed by acetylchloride(0.044 mmol). The reaction mixture was concentrated by rotaryevaporation. The residue was dissolved in ethanol (0.2 mL) andhydrolyzed with 1N aqueous NaOH (0.1 mL) at room temperature for 30minutes. Solvents were removed by rotary evaporation and the resultingresidue was dissolved in 50% acetic acid in water (1.5 mL), filtered andpurified by preparative HPLC to give the TFA salt of the title compound(12 mg). (m/z): [M+H]⁺ calcd for C₂₄H₃₆N₂O₂, 385.29; found 385.2.

Examples 8-14

Using processes similar to that of Example 7, except replacing theacetylchloride with 0.044 mmol of the appropriate acyl chloride, the TFAsalts of the compounds of Examples 3-5 were prepared.

Example 8

N-cyclohexylmethyl-N-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}propionamide(7.1 mg) (m/z): [M+H]⁺ calcd for C₂₅H₃₈N₂O₂, 399.30; found 399.2.

Example 9

cyclopentanecarboxylic acidcyclohexylmethyl-{2-[3-endo-(3-hydroxy-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}amide(16.4 mg) (m/z): [M+H]⁺ calcd for C₂₈H₄₂N₂O₂, 439.34; found 439.2.

Example 10

cyclohexanecarboxylic acidcyclohexylmethyl-{2-[3-endo-(3-hydroxy-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}amide(14 mg) (m/z): [M+H]⁺ calcd for C₂₉H₄₄N₂O₂, 453.35; found 453.4.

Example 11

N-cyclohexylmethyl-3-cyclopentyl-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}propionamide(11.4 mg) (m/z): [M+H]⁺ calcd for C₃₀H₄₆N₂O₂, 467.37; found 467.4.

Example 12

N-cyclohexylmethyl-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}-3-methylbutyramide(14.1 mg) (m/z): [M+H]⁺ calcd for C₂₇H₄₂N₂O₂, 427.33; found 427.4.

Example 13

N-cyclohexylmethyl-2-hydroxy-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}acetamide(10.8 mg) (m/z): [M+H]⁺ calcd for C₂₄H₃₆N₂O₃, 401.28; found 401.2.

Example 14

N-cyclohexylmethyl-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylacetamide(16.8 mg) (m/z): [M+H]⁺ calcd for C₃₀H₄₀N₂O₂, 461.32; found 461.2.

Example 15: Synthesis of1-[(cyclohexylmethyl-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}carbamoyl)methyl]cyclohexyl}-aceticacid

To a solution of the TFA salt of3-endo-{8-[2-(cyclohexylmethylamino)-ethyl]-8-azabicyclo[3.2.1]oct-3-yl-phenolprepared by the method of Preparations 1 and 3 (24 mg, 0.042 mmol) indichloromethane (0.4 mL) at room temperature was addedN,N-diisopropylethylamine (22 mg, 0.17 mmol) followed by1,1-cyclohexanediacetic anhydride (0.042 mmol). After 20 minutes thereaction went to completion and the reaction mixture was concentrated.The residue was dissolved in methanol and hydrolyzed with 1N aqueousNaOH (0.1 mL) at room temperature for 30 minutes. Solvents were removedand the resulting residue was dissolved in 50% acetic acid in water (1.5mL), filtered and purified by preparative HPLC to give the TFA salt ofthe title compound. (m/z): [M+H]⁺ calcd for C₃₂H₄₈N₂O₄, 525.37; found525.2.

Examples 16-17

Using processes similar to that of Example 15, except replacing the1,1-cyclohexanediacetic anhydride with 0.042 mmol of the listedanhydride, the TFA salts of the compounds of Examples 16 and 17 wereprepared.

Example 16

{1-[(cyclohexylmethyl-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}carbamoyl)methyl]cyclopentyl}aceticacid reagent: 3,3-tetramethyleneglutaric anhydride (m/z): [M+H]⁺ calcdfor C₃₁H₄₆N₂O₄, 511.36; found 511.2.

Example 17

2-(cyclohexylmethyl-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}carbamoyl)cyclohexanecarboxylicacid reagent: 1,2-cyclohexanedicarboxylic anhydride (m/z): [M+H]⁺ calcdfor C₃₀H₄₄N₂O₄, 497.34; found 497.2.

Example 18A:N-cyclohexylmethyl-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}succinamicacid

To a solution of3-endo-{8-[2-(cyclohexylmethylamino)-ethyl]-8-azabicyclo[3.2.1]oct-3-yl-phenolprepared by the method of Preparations 1 and 3 and converted to freebase form (83 mg, 0.24 mmol) in dichloromethane (2.5 mL) at roomtemperature was added N,N-diisopropylethylamine (124 mg, 0.96 mmol)followed by 3-carbomethoxypropionyl chloride (72 mg, 0.48 mmol). Theresulting mixture was stirred at room temperature for about 10 minutesand then concentrated, dissolved in ethanol (2 mL) and hydrolyzed withlithium hydroxide monohydrate (61 mg) in water (2 mL) for about 30minutes. The reaction mixture was then concentrated, dissolved in 50%acetic acid in water (10 mL), filtered, and purified by reversed phasepreparative HPLC to give the TFA salt of the title compound. (m/z):[M+H]⁺ calcd for C₂₆H₃₈N₂O₄, 443.29; found 443.2.

Example 18B:N-cyclohexylmethyl-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}succinamicacid

To a solution of the bis TFA salt of3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}phenol,prepared by the method of Preparation 4 and analogously to that ofPreparation 11 (70 mg, 0.12 mmol) in dichloromethane (0.4 mL) at roomtemperature was added N,N-diisopropylethyl amine (62 mg, 0.48 mmol)followed by succinic anhydride (0.16 mmol). The resulting mixture wasstirred at room temperature for about 10 minutes before it wasconcentrated. The residue was then redissolved in 50% acetic acid inwater (10 mL), filtered, and purified by reverse phase preparative HPLC.The residue was freeze dried, and then the solid was dissolved in amixture of MeOH (1.0 mL) and water (2.0 mL) and treated with lithiumhydroxide monohydrate (30 mg) at ambient temperature for thirty minutes.The product was concentrated, dissolved in 50% acetic acid in water (10mL), filtered, and purified by reverse phase preparative HPLC to givethe TFA salt of the title compound (28.9 mg). (m/z): [M+H]⁺ calcd forC₂₆H₃₈N₂O₄, 443.29; found 443.5. ¹H NMR (CD₃OD, 300 MHz) δ (ppm):7.10-7.155 (m, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.85 (s, 1H), 6.63 (d, J=8.1Hz, 1H), 4.01 (brs, 2H), 3.71-3.79 (m, 2H), 3.26-3.28 (m, obscure 2H),3.10-3.12 (m, 3H), 2.67 (s, 4H), 2.48-2.52 (m, 4H), 2.04-2.08 (m, 2H),1.706-1.875 (m, 8H), 1.238-1.30 (m, 3H), 0.98-1.03 (m, 2H).

Example 19: Synthesis of4-(cyclohexylmethyl-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}carbamoyl)-3,3-dimethylbutyricacid

To a solution of the TFA salt of3-endo-{8-[2-(cyclohexylmethylamino)-ethyl]-8-azabicyclo[3.2.1]oct-3-yl-phenolprepared by the method of Preparations 1 and 3 (25 mg, 0.044 mmol) indichloromethane (0.4 mL) at room temperature was addedN,N-diisopropylethylamine (23 mg, 0.18 mmol) followed by 3,3-dimethylglutaric anhydride (9 mg, 0.07 mmol). The reaction was stirred at roomtemperature overnight. The reaction mixture was concentrated by rotaryevaporation, dissolved in 50% acetic acid in water (1.5 mL), filtered,and purified by preparative HPLC to give the TFA salt of the titlecompound (13.3 mg). (m/z): [M+H]⁺ calcd for C₂₉H₄₄N₂O₄, 485.34; found485.4.

Example 20: Synthesis of[(cyclohexylmethyl-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}carbamoyl)methanesulfonyl]aceticacid

To a solution of methoxycarbonylmethanesulfonyl acetic acid (10 mg,0.525 mmol) in dimethylacetamide (1 mL) at room temperature was added1,1′-carbonyldiimidazole (114 mg, 0.7 mmol). Two hours later, to thisstirred mixture was added a solution of the TFA salt of3-endo-{8-[2-(cyclohexylmethylamino)-ethyl]-8-azabicyclo[3.2.1]oct-3-yl-phenolprepared by the method of Preparations 1 and 3 (100 mg, 0.175 mmol) andN,N-diisopropylethylamine (91 mg, 0.7 mmol) in dimethylacetamide (1 mL).The reaction mixture was heated to 65° C. for 3 hours and then stirredat room temperature overnight. The reaction mixture was diluted withethanol (2.0 mL) and treated with a solution of lithium hydroxidemonohydrate (150 mg) in water (1.5 mL) for about 30 minutes. Thesolvents were removed and the residue was dissolved in 50% acetic acidin water (10 mL), filtered and purified by reversed phase preparativeHPLC to give the TFA salt of the title compound as a white solid (28.3mg). (m/z): [M+H]⁺ calcd for C₂₆H₃₈N₂O₆S, 507.26; found 507.2. ¹H NMR(CD₃OD, 300 MHz) δ (ppm): 7.1-7.17 (m, 1H), 6.87-6.94 (m, 2H), 6.63-6.72(m, 1H), 4.63 (s, 2H), 4.44 (s, 2H), 4.07 (brs, 2H), 3.80 (t, J=5.7 Hz,2H), 3.34 (d, J=7.2 Hz, obscure 2H), 3.13-3.2 (m, 3H), 2.51-2.53 (m,4H), 1.69-1.88 (m, 8H), 1.19-1.33 (m, 3H), 0.92-1.06 (m, 2H).

Example 21: Synthesis ofN-cyclohexylmethyl-N-{2-[3-endo-(3-hydroxy-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}malonamicacid

To a solution of malonic acid mono-tert-butyl ester (84 mg, 0.53 mmol)in dimethylacetamide (1.0 mL) at room temperature was added1,1′-carbonyldiimidazole (114 mg, 0.7 mmol). Two hours later, to thisstirred mixture was added a solution of the TFA salt of3-endo-{8-[2-(cyclohexylmethylamino)-ethyl]-8-azabicyclo[3.2.1]oct-3-yl-phenolprepared by the method of Preparations 1 and 3 (100 mg, 0.175 mmol) andN,N diisopropylethylamine (91 mg, 0.7 mmol) in dimethylacetamide (1 mL).The resulting reaction mixture was heated to 65° C. for 3 hours andstirred at room temperature overnight. The reaction mixture was dilutedwith ethyl acetate, and washed successively with water and brine. Thereaction mixture was dried over sodium sulfate, filtered, andconcentrated to give a yellowish oil and further dried under vacuum for30 min. The residue was treated with trifluoroacetic acid (5 mL) at roomtemperature for 10 minutes. The reaction mixture was diluted with water(5 mL), filtered, and purified by reversed phase preparative HPLC togive the TFA salt of the title compound as a white solid (51.5 mg).(m/z): [M+H]⁺ calcd for C₂₅H₃₆N₂O₄, 429.28; found 429.2. ¹H NMR (CD₃OD,300 MHz) δ (ppm): 7.11-7.17 (m, 1H), 6.87-6.94 (m, 2H), 6.63-6.66 (m,1H), 4.08 (brs, 2H), 3.77-3.81 (m, 2H), 3.58 (deformed s, 1H), 3.24 (d,J=6.9 Hz, obscure 2H), 3.14-3.18 (m, 3H), 2.51-2.54 (m, 4H), 2.05-2.09(m, 2H), 1.69-1.89 (m, 8H), 1.24-1.31 (m, 3H), 0.98-1.03 (m, 2H).

Example 22: Synthesis of3-sec-butyl-1-cyclohexylmethyl-1-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-urea

To a solution of the TFA salt of3-endo-{8-[2-(cyclohexylmethylamino)-ethyl]-8-azabicyclo[3.2.1]oct-3-yl-phenolprepared by the method of Preparations 1 and 3 (30 mg, 0.053 mmol) indimethylformamide (0.2 mL) at room temperature was addedN,N-diisopropylethylamine (27 mg, 0.21 mmol) followed by sec-butylisocyanate (0.079 mmol). The resulting mixture was shaken at roomtemperature overnight, concentrated, dissolved in 50% acetic acid inwater (1.5 mL), filtered, and purified by preparative HPLC to give theTFA salt of the title compound (17.8 mg). (m/z): [M+H]⁺ calcd forC₂₇H₄₃N₃O₂, 442.35; found 442.4.

Examples 23-28

Using processes similar to that of Example 22, except replacing thesec-butyl isocyanate with 0.079 mmol of the listed isocyanate, the TFAsalts of the compounds of Examples 23 to 28 were prepared.

Example 23

3-benzyl-1-cyclohexylmethyl-1-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}urea(13.2 mg); reagent: benzylisocyanate (m/z): [M+H]⁺ calcd for C₃₀H₄₁N₃O₂,476.33; found 476.2.

Example 24

3-benzo[1,3]dioxol-5-yl-1-cyclohexylmethyl-1-{2-[3-endo-(3-hydroxy-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}urea(12.0 mg); reagent: 3,4-methylenedioxyphenyl isocyanate (m/z): [M+H]⁺calcd for C₃₀H₃₉N₃O₄, 506.30; found 506.2.

Example 25

1-cyclohexylmethyl-3-(3-fluorophenyl)-1-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}urea(14.3 mg); reagent: 3-fluorophenyl isocyanate (m/z): [M+H]⁺ calcd forC₂₉H₃₈FN₃O₂, 480.30; found 480.2.

Example 26

1-cyclohexylmethyl-1-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}-3-pentylurea(14.6 mg); reagent: pentylisocyanate (m/z): [M+H]⁺ calcd for C₂₈H₄₅N₃O₂,456.36; found 456.4.

Example 27

1-cyclohexylmethyl-3-(4-fluorobenzyl)-1-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}urea(13.6 mg); reagent: 4-fluorobenzyl isocyanate (m/z): [M+H]⁺ calcd forC₃₀H₄₀FN₃O₂, 494.34; found 494.2.

Example 28

1-cyclohexylmethyl-3-(4-difluoromethoxyphenyl)-1-{2-[3-endo-(3-hydroxy-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}urea(21.8 mg); reagent: 4-difluoromethoxyphenyl isocyanate (m/z): [M+H]⁺calcd for C₃₀H₃₉F₂N₃O₃, 528.31; found 528.2.

Example 29A: Synthesis ofN-cyclohexylmethyl-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}succinamicacid methyl ester

To a solution of3-endo-{8-[2-(cyclohexylmethylamino)-ethyl]-8-azabicyclo[3.2.1]oct-3-yl-phenolprepared by the method of Preparations 1 and 3 (114 mg, 0.20 mmol) indichloromethane (1 mL) at room temperature was addedN,N-diisopropylethylamine (103 mg, 0.80 mmol) followed by a solution of3-carbomethoxypropionyl chloride (0.20 mmol) in dichloromethane (0.3mL). The resulting mixture was stirred at room temperature for about 10minutes, concentrated, redissolved in 50% acetic acid in water (5 mL),filtered, and purified by reversed phase preparative HPLC to give theTFA salt of the title compound as a white salt (46.4 mg). (m/z): [M+H]⁺calcd for C₂₇H₄₀N₂O₄, 457.31; found 457.3.

Example 29B: Synthesis ofN-cyclohexylmethyl-N-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}succinamicacid methyl ester

To a solution of the bis TFA salt of3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}phenol,prepared by the method of Preparation 4 and analogously to that ofPreparation 11 (88 mg, 0.15 mmol) in dichloromethane (0.4 mL) at roomtemperature was added N,N-diisopropylethyl amine (80 mg, 0.62 mmol)followed by a DCM solution (0.15 mL) of 3-carbomethoxypropionyl chloride(0.18 mmol). The resulting mixture was stirred at room temperature forabout 10 minutes. Mass spectrometry (electron spray) showed startingmaterial was still present. Additional 3-carbomethoxypropionyl chloride(0.05 mmol) was added. When the reaction was judged complete byanalytical HPLC, the reaction mixture was concentrated, dissolved in 50%acetic acid in water (10 mL), filtered, and purified by reversed phasepreparative HPLC to give the TFA salt of the title compound as a whitesolid (44.7 mg). (m/z): [M+H]⁺ calcd for C₂₇H₄₀N₂O₄, 457.31; found457.5. ¹H NMR (CD₃OD, 300 MHz) δ (ppm): 7.10-7.15 (m, 1H), 6.90 (d,J=7.8 Hz, 1H), 6.85 (s, 1H), 6.63 (d, J=7.8 Hz, 1H), 4.02 (brs, 2H),3.70-3.71 (m, 2H), 3.63 (s, 3H), 3.26-3.28 (m, obscure 2H), 3.08-3.11(m, 3H), 2.67-2.71 (m, 4H), 2.47-2.49 (m, 4H), 2.04-2.1 (m, 2H),1.708-1.878 (m, 8H), 1.21-1.38 (m, 3H), 0.95-1.03 (m, 2H).

Example 30: Synthesis ofN-cyclohexylmethyl-N-{2-[3-endo-(3-hydroxy-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-methanesulfonylacetamide

To a solution of methanesulfonylacetic acid (0.10 mmol) indimethylformamide (0.2 mL) at room temperature was added1,1′-carbonyldiimidazole (21 mg, 0.13 mmol). The reaction mixture wasshaken for about one hour before a mixture of the TFA salt of3-endo-{8-[2-(cyclohexylmethylamino)-ethyl]-8-azabicyclo[3.2.1]oct-3-yl-phenol(prepared by the method of Preparations 1 and 3) (30 mg, 0.053 mmol) andN,N-diisopropylethylamine (0.10 mmol) in dimethylformamide (0.3 mL) wasadded. The resulting mixture was stirred at room temperature overnight,concentrated, diluted with 50% acetic acid in water (8 mL), filtered,and purified by reversed phase preparative HPLC to give the TFA salt ofthe title compound (7.5 mg). (m/z): [M+H]⁺ calcd for C₂₅H₃₈N₂O₄S,463.27; found 463.5.

Example 31: Synthesis ofN-cyclohexylmethyl-N-{2-[3-endo-(3-hydroxy-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}succinamide

To a solution ofN-cyclohexylmethyl-N-{2-[3-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}succinamicacid, the product of Example 18 (95 mg, 0.17 mmol) in dimethylacetamide(0.2 mL) at room temperature was added 1,1′-carbonyldiimidazole (165 mg,1.02 mmol). One hour later, ammonium acetate (79 mg, 1.02 mmol) wasadded followed by N,N-diisopropylethylamine (132 mg, 1.02 mmol). Theresulting mixture was shaken at room temperature overnight, dissolved in50% acetic acid in water (10 mL), filtered, and purified by reversedphase preparative HPLC to give the TFA salt of the title compound (5.6mg). (m/z): [M+H]⁺ calcd for C₂₆H₃₉N₃O₃, 442.31; found 442.5.

Example 32: Synthesis of1-cyclohexylmethyl-3-(3,4-dimethoxyphenyl)-1-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}urea

To a solution of the TFA salt of3-endo-{8-[2-(cyclohexylmethylamino)-ethyl]-8-azabicyclo[3.2.1]oct-3-yl-phenolprepared by the method of Preparations 1 and 3 (30 mg, 0.05 mmol) indimethylformamide (0.2 mL) at room temperature was addedN,N-diisopropylethylamine (27 mg, 0.21 mmol) followed by3,4-dimethoxyphenyl isocyanate (14 mg, 0.078 mmol). The resultingmixture was allowed to stand at room temperature overnight, concentratedby rotary evaporation, redissolved in 50% acetic acid in water (1.5 mL),filtered, and purified by preparative HPLC to give the TFA salt of thetitle compound (13.5 mg). (m/z): [M+H]⁺ calcd for C₃₁H₄₃N₃O₄, 522.34;found 522.2.

Examples 33-38

Using the general method of Example 7, except replacing thecyclohexylamine intermediate with the appropriate substitutedbenzylamine prepared as in Preparation 3, using the3-endo-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol intermediate prepared as inPreparation 1, and replacing the acetylchloride with the appropriateacyl chloride, the TFA salts of the compounds of Examples 33-38 wereprepared.

Example 33

N-(3-fluorobenzyl)-2-hydroxy-N-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}acetamide(9.6 mg) (m/z): [M+H]⁺ calcd for C₂₄H₂₉FN₂O₃, 413.23; found 413.2.

Example 34

N-(3-fluorobenzyl)-2-hydroxy-N-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}succinamicacid (12.0 mg) (m/z): [M+H]⁺ calcd for C₂₆H₃₁FN₂O₄, 455.24; found 455.2.

Example 35

N-(3-fluorobenzyl)-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}-3-methylbutyramide(9.9 mg) (m/z): [M+H]⁺ calcd for C₂₇H₃₅FN₂O₂, 439.28; found 439.2.

Example 36

N-(2,6-difluorobenzyl)-2-hydroxy-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}acetamide(9.0 mg) (m/z): [M+H]⁺ calcd for C₂₄H₂₈F₂N₂O₃, 431.22; found 431.2.

Example 37

N-(2,6-difluorobenzyl)-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}-3-methylbutyramide(13.1 mg) (m/z): [M+H]⁺ calcd for C₂₇H₃₄F₂N₂O₂, 457.27; found 457.2.

Example 38

N-(2,6-difluorobenzyl)-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}acetamide(11.7 mg) (m/z): [M+H]⁺ calcd for C₂₄H₂₈F₂N₂O₂, 415.22; found 415.2.

Examples 39-42

Using the general method of Example 21, except replacing thecyclohexylamine intermediate with the appropriate substitutedbenzylamine prepared as in Preparation 3, using the3-endo-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol intermediate prepared as inPreparation 1, and replacing the malonic acid mono tert-butyl ester withmethanesulphonyl acetic acid in Examples 40 and 42, the TFA salts of thecompounds of Examples 39-42 were prepared.

Example 39

N-(3-fluorobenzyl)-N-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}malonamicacid (11.4 mg) (m/z): [M+H]⁺ calcd for C₂₅H₂₉FN₂O₄, 441.22; found 441.2.

Example 40

N-(3-fluorobenzyl)-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}-2-methanesulfonyl-acetamide(25.0 mg) (m/z): [M+H]⁺ calcd for C₂₅H₃₁FN₂O₄S, 475.21; found 475.2.

Example 41

N-(2,6-difluorobenzyl)-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}malonamicacid (11.1 mg) (m/z): [M+H]⁺ calcd for C₂₅H₂₈F₂N₂O₄, 459.21.;found459.2.

Example 42

N-(2,6-difluorobenzyl)-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}-2-methanesulfonyl-acetamide(11.1 mg) (m/z): [M+H]⁺ calcd for C₂₅H₃₀F₂N₂O₄S, 493.20; found 493.2.

Example 43: Synthesis ofN-(4-fluorobenzyl)-2-hydroxy-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-icyclo[3.2.1]oct-8-yl]ethyl}acetamide

To a solution of the bis TFA salt of3-endo-{8-[2-(4-fluorobenzylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-phenol,prepared by the methods of Preparations 4 and 3 (30 mg, 0.05 mmol) indichloromethane (0.2 mL) at room temperature was addedN,N-diisopropylethylamine (26 mg, 0.2 mmol) followed by acetoxyacetylchloride (0.075 mmol). After the reaction went to completion asindicated by mass spectrometric analysis, the mixture was concentratedby rotary evaporation and the residues were dissolved in EtOH (0.2 mL)and hydrolyzed with lithium hydroxide monohydrate (17 mg) in water (0.2mL) at room temperature for 30 minutes. Solvents were removed by rotaryevaporation and the resulting residue was dissolved in 50% acetic acidin water (1.5 mL), filtered and purified by preparative HPLC to give theTFA salt of the title compound (16.6 mg). (m/z): [M+H]⁺ calcd forC₂₄H₂₉FN₂O₃, 413.23; found 413.2.

Example 44: Synthesis ofN-(4-chlorobenzyl)-2-hydroxy-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-icyclo[3.2.1]oct-8-yl]ethyl}acetamide

Following the procedure of Example 43, using the appropriate substitutedbenzylamine of Preparation 3, the TFA salt of the title compound (19.1mg) was obtained. (m/z): [M+H]⁺ calcd for C₂₄H₂₉ClN₂O₃, 429.20; found429.2.

Example 45: Synthesis of2-hydroxy-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-N-(4-trifluoromethylbenzyl)acetamide

Following the procedure of Example 43, using the substituted benzylamineprepared according to Preparation 11, the TFA salt of the title compound(19.5 mg) was obtained. (m/z): [M+H]⁺ calcd for C₂₅H₂₉F₃N₂O₃, 463.22;found 463.2.

Example 46A: Synthesis of3-endo-(8-{2-[benzyl-(2-hydroxyacetyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide

To a solution of the bis TFA salt of3-endo-[8-(2-benzylaminoethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]benzamide,prepared by the method of Preparations 5 and 6 (111 mg, 0.188 mmol) indichloromethane (0.94 mL) at −20° C. was added N,N-diisopropylethylamine(97 mg, 0.75 mmol) followed by acetoxyacetylchloride (27 mg, 0.29 mmol)in dichloromethane (0.5 mL). The reaction mixture was stirred at −20° C.to −10° C. for about 30 minutes before it was quenched with saturatedsodium bicarbonate and then extracted with DCM. The organic layer waswashed with brine, dried over sodium sulfate, filtered and concentratedto give a yellowish oil which was dissolved in EtOH (1.0 mL) and treatedwith lithium hydroxide monohydrate (24 mg, 0.56 mmol) in water (0.5 mL)at room temperature for 30 minutes. The solvents were removed by rotaryevaporation and the resulting residue was dissolved in 50% acetic acidin water (10 mL), filtered, and purified by preparative HPLC to give theTFA salt of the title compound (58.7 mg). (m/z): [M+H]⁺ calcd forC₂₅H₃₁N₃O₃, 422.25; found 422.3.

Example 46B: Synthesis of3-endo-(8-{2-[benzyl-(2-hydroxyacetyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide

To a solution of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)benzamide, preparedby the method of Preparation 13 (102 mg, 0.44 mmol) in dichloromethane(2 mL) at ambient temperature was added a solution of acetic acid[benzyl-(2-oxo-ethyl)carbamoyl]methyl ester (164 mg, 0.66 mmol) indichloromethane (2 mL) followed by sodium triacetoxyborohydride (131mg). The reaction mixture was stirred at ambient temperature for aboutthirty minutes and judged complete by mass spectrometric analysis. Thereaction was then concentrated and redissolved in EtOH (6 mL) andtreated with lithium hydroxide monohydride (111 mg) in water (4 mL) forabout thirty minutes. Then, the mixture was concentrated, redissolved in50% acetic acid in water (10 mL), filtered, and purified by reversephase preparative HPLC to give the TFA salt of the title compound (115.7mg). (m/z): [M+H]⁺ calcd for C₂₅H₃₁N₃O₃, 422.25; found 422.4; ¹H NMR(CD₃OD, 300 MHz) δ (ppm) 8.0 (s, 1H), 7.68-7.75 (m, 2H), 7.26-7.47 (m,6H), 4.57 (s, 2H), 4.37 (s, 2H), 4.08 (brs, 2H), 3.72 (t, J=5.7 Hz, 2H),3.05 (t, J=5.4 Hz, 2H), 2.59-2.62 (m, 4H), 1.99-2.03 (m, 2H), 1.74-1.81(m, 2H).

Example 47: Synthesis ofN-{2-[3-endo-(3-carbamoylphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}-N-cyclohexylmethyl-succinamicacid

To a solution of the bis TFA salt of3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl}benzamideprepared by the method of Preparations 5 and 7 (114 mg, 0.19 mmol) indichloromethane (0.95 mL) at room temperature was addedN,N-diisopropylethyl amine (98 mg, 0.76 mmol). The resulting mixture wasthen cooled to −30° C. before a solution of 3-carbomethoxypropionylchloride (30 mg, 0.20 mmol) in DCM (0.5 mL) was added. After thereaction went to completion, the mixture was concentrated. The residuewas redissolved in EtOH (2 mL) and treated with lithium hydroxidemonohydrate (32 mg) in water (1 mL) for about 30 minutes. The mixturewas concentrated, dissolved in 50% acetic acid in water (10 mL),filtered and purified by reversed phase preparative HPLC to give the TFAsalt of the title compound (63.2 mg). (m/z): [M+H]⁺ calcd forC₂₇H₃₉N₃O₄, 470.30; found 470.5.

Example 48: Synthesis of3-endo-(8-{2-[cyclohexylmethyl-(2-hydroxyacetyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide

To a solution of the bis TFA salt of3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl}benzamideprepared by the method of Preparations 13 and 9 (734 mg, 1.23 mmol) indichloromethane (5 mL) at room temperature was addedN,N-diisopropylethyl amine (635 mg, 4.9 mmol). The resulting mixture wascooled to −20° C. before a solution of acetoxyacetyl chloride (184 mg,1.35 mmol) in DCM (2 mL) was added. Five minutes later, the reactionwent to completion as confirmed by mass spectrometric analysis. Thereaction mixture was concentrated, dissolved in EtOH (15 mL) and treatedwith lithium hydroxide monohydrate (309 mg) in water (5 mL) for about 30minutes. The reaction mixture was then concentrated, dissolved in 50%acetic acid in water (15 mL), filtered and purified by reversed phasepreparative HPLC to give the TFA salt of the title compound (585.9 mg).(m/z): [M+H]⁺ calcd for C₂₅H₃₇N₃O₃, 428.29; found 428.2. ¹H NMR (CD₃OD,300 MHz) δ (ppm): 8.0 (s, 1H), 7.68-7.74 (m, 2H), 7.42-7.47 (t, J=8.1Hz, 1H), 4.27 (s, 2H), 4.09 (brs, 2H), 3.72 (t, J=5.7 Hz, 2H), 3.2-3.35(m, obscure 1H), 3.09-3.14 (m, 4H), 2.59-2.62 (m, 4H), 2.07-2.12 (m,2H), 1.62-1.83 (m, 8H), 1.15-1.35 (m, 3H), 0.87-1.16 (m, 2H).

Example 49: Synthesis of3-endo-{8-[2-(cyclohexylmethyl-phenylacetylamino)-ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamide

To a solution of the bis TFA salt of3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl}benzamideprepared by the method of Preparations 5 and 7 (112 mg, 0.19 mmol) indichloromethane (1 mL) at room temperature was addedN,N-diisopropylethyl amine (97 mg, 0.75 mmol). The resulting mixture wasthen cooled to −40° C. before a solution of phenylacetyl chloride (32mg, 0.21 mmol) in DCM (0.1 mL) was added. The resulting mixture wasstirred at a temperature between −40° C. to −20° C. for about 30minutes. The reaction was judged complete according to massspectrometric analysis. After concentration, the residue was redissolvedin 50% acetic acid in water (10 mL), filtered and purified by reversedphase preparative HPLC to give the TFA salt of the title compound (27.5mg). (m/z): [M+H]⁺ calcd for C₃₁H₄₁N₃O₂, 488.33; found 488.8.

Example 50: Synthesis ofN-{2-[3-endo-(3-carbamoyl-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}-N-cyclohexylmethyl-succinamicacid methyl ester

To a solution of the bis TFA salt of3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl}benzamideprepared by the method of Preparations 5 and 7 (97 mg, 0.16 mmol) indichloromethane (0.8 mL) at room temperature was addedN,N-diisopropylethylamine (83 mg, 0.64 mmol). The resulting mixture wasthen cooled to −20° C. before a solution of 3-carbomethoxypropionylchloride (29 mg, 0.19 mmol) in DCM (0.1 mL) was added. followed byanother portion of 3-carbomethoxypropionyl chloride (0.20 mmol) in DCM(0.3 mL). After 30 minutes, LC-MS analysis of an aliquot showed desiredmolecular weight. The reaction mixture was then concentrated,redissolved in 50% acetic acid in water (8 mL), filtered, and purifiedby reversed phase preparative HPLC to give the TFA salt of the titlecompound as a white solid (46.4 mg). (m/z): [M+H]⁺ calcd for C₂₈N₄₁N₃O₄,484.32; found 484.5.

Example 51: Synthesis of3-endo-{8-[2-(3-sec-butyl-1-cyclohexylmethyl-ureido)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamide

Following the method of Example 32, the bis TFA salt of3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl}benzamideprepared by the method of Preparations 5 and 9 (30 mg, 0.05 mmol) wasreacted with sec-butylisocyanate (0.075 mmol). Purification yielded theTFA salt of the title compound (24.2 mg). (m/z): [M+H]⁺ calcd forC₂₈H₄₄N₄O₂, 469.35; found 469.4.

Example 52: Synthesis of3-endo-{8-[2-(1-cyclohexylmethyl-3-pentylureido)-ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamide

To a solution of the bis TFA salt of3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl}benzamideprepared by the method of Preparations 5 and 9 (30 mg, 0.05 mmol) in DMF(0.4 mL) at room temperature was added N,N-diisopropylethylamine (27 mg,0.20 mmol) followed by pentylisocyanate (0.075 mmol). The resultingmixture was shaken at room temperature overnight, concentrated,dissolved in 50% acetic acid in water (1.5 mL), filtered, and purifiedby preparative HPLC to provide the TFA salt of the title compound (23.3mg). (m/z): [M+H]⁺ calcd for C₂₉H₄₆N₄O₂, 483.37; found 483.4.

Examples 53-55

Using the general method of Example 52, replacing the pentylisocyanatewith the appropriate isocyanate, the TFA salts of the compounds ofExamples 53-55 were prepared.

Example 53

3-endo-(8-{2-[1-cyclohexylmethyl-3-(4-fluorobenzyl)-ureido]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide(30.3 mg) (m/z): [M+H]⁺ calcd for C₃₁H₄₁FN₄O₂, 521.33; found 521.2.

Example 54

3-endo-{8-[2-(3-benzo[1,3]dioxol-5-yl-1-cyclohexylmethylureido)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamide(24.5 mg) (m/z): [M+H]⁺ calcd for C₃₁H₄₀N₄O₄, 533.31; found 533.2; ¹HNMR (CD₃OD, 300 MHz) δ (ppm) 7.97 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.66(d, J=8.1 Hz, 1H), 7.42 (dd, J=7.8 Hz, 1H), 3.90-3.99 (m, 3H), 3.60 (t,J=4.8 Hz, 2H), 3.25-3.29 (m, 1H, overlap with solvent), 3.02-3.09 (m,4H), 2.55-2.58 (m, 4H), 2.03-2.07 (m, 2H), 1.63-1.78 (m, 8H), 1.07-1.25(m, 9H), 0.92-1.01 (m, 2H).

Example 55

3-endo-{8-[2-(1-cyclohexylmethyl-3-isopropylureido)ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl}benzamide(24.5 mg) (m/z): [M+H]⁺ calcd for C₂₇H₄₂N₄O₂, 455.33; found 455.4; ¹HNMR (CD₃OD, 300 MHz) δ (ppm) 7.97 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.66(d, J=8.1 Hz, 1H), 7.42 (dd, J=7.8 Hz, 1H), 3.90-3.99 (m, 3H), 3.60 (t,J=4.8 Hz, 2H), 3.25-3.29 (m, 1H, overlap with solvent), 3.02-3.09 (m,4H), 2.55-2.58 (m, 4H), 2.03-2.07 (m, 2H), 1.63-1.78 (m, 8H), 1.07-1.25(m, 9H), 0.92-1.01 (m, 2H).

Example 56: Synthesis of3-endo-(8-{2-[cyclohexylmethyl-(2-methanesulfonyl-acetyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamide

To a solution of methanesulfonylacetic acid (90 mg, 0.65 mmol) in DMF(0.2 mL) was added 1,1′-carbonyldiimidazole (105 mg, 0.65 mmol). Onehour later,3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl}benzamideprepared by the method of Preparations 12 and 9 (60 mg, 0.16 mmol) wasadded followed by N,N-diisopropylethylamine (84 mg, 0.65 mmol). Theresulting mixture was heated to 60° C. for two hours then cooled down toroom temperature for 60 h. Then it was concentrated, dissolved in 50%acetic acid in water (3 mL), filtered and purified by preparative HPLCto give the TFA salt of the title compound (35.1 mg). (m/z): [M+H]⁺calcd for C₂₆H₃₉N₃O₄S, 490.27; found 490.2. ¹H NMR (CD₃OD, 300 MHz) δ(ppm): 7.98 (s, 1H), 7.66-7.74 (m, 2H), 7.41-7.46 (m, 1H), 4.77 (s, 2H),4.38 (brs, 2H), 3.78-3.82 (m, 2H), 3.04-3.33 (m, obscure 5H), 3.21 (s,3H), 2.57-2.61 (m, 4H), 2.07-2.10 (m, 2H), 1.66-1.79 (m, 8H), 1.22-1.29(m, 3H), 0.94-1.01 (m, 2H).

Example 57: Synthesis of3-endo-(8-{2-[(2-aminoacetyl)-cyclohexylmethyl-amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamide

To a solution of n-tert-butoxycarbonylglycine (34 mg, 0.20 mmol) in DMF(0.2 mL) at room temperature was added 1,1′-carbonyldiimidazole (32 mg,0.2 mmol). After shaking at room temperature for 2 hours, to thismixture was added the bis TFA salt of3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamideprepared by the method of Preparations 12 and 9 (30 mg, 0.05 mmol) andN,N-diisopropylethylamine (26 mg, 0.2 mmol). The resulting reactionmixture was shaken at room temperature overnight. After concentration,the residue was treated with 50% TFA in DCM (1 mL). The mixture wasconcentrated and the residue was dissolved in 50% acetic acid in water(1.5 mL), filtered and purified by reversed phase preparative HPLC togive the bis TFA salt of the title compound (15.9 mg). (m/z): [M+H]⁺calcd for C₂₅H₃₈N₄O₂, 427.31; found 427.2.

Example 58A: Synthesis of3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamide

To a solution of (S)-2,2-dimethyl-[1,3]dioxolane-4-carboxylic acid (98mg, 0.67 mmol) in DMF (0.2 mL) at room temperature was added1,1′-carbonyldiimidazole (109 mg, 0.67 mmol). After being stirred atroom temperature for one hour, to this mixture was added the bis TFAsalt of3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamideprepared by the method of Preparations 12 and 9 (100 mg, 0.167 mmol) andN,N-diisopropylethylamine (87 mg, 0.67 mmol). The reaction mixture washeated at 60° C. for two hours and then at room temperature for 72hours. The mixture was diluted with water and extracted with ethylacetate. The organic layer was sequentially washed with water (2×2 mL),1N NaOH (2 mL), brine (2 mL), dried over sodium sulfate, filtered, andconcentrated. The resulting residue was then dissolved in acetic acid(1.5 mL) and water (0.5 mL) and heated to 65° C. overnight. The mixturewas concentrated by rotary evaporation, redissolved in 50% acetic acidin water (3.0 mL), filtered and purified by reversed phase preparativeHPLC to give the TFA salt of the title compound (15.5 mg). (m/z): [M+H]⁺calcd for C₂₆H₃₉N₃O₂, 458.30; found 458.2. ¹H NMR (CD₃OD, 300M Hz) δ(ppm): 7.98 (s, 1H), 7.67-7.73 (m, 2H), 7.40-7.45 (m, 1H), 4.57 (t,J=5.4 Hz, 1H), 3.94-4.12 (m, 3H), 3.69-3.72 (m, 2H), 3.50-3.58 (m, 1H),3.35-3.43 (m, 1H), 3.20-3.27 (obscure 2H, partially overlap withsolvent), 3.12-3.15 (m, 2H), 2.52 (brs, 4H), 1.98-2.02 (m, 2H),1.61-1.70 (m, 8H), 1.09-1.22 (m, 3H), 0.88-0.95 (m, 2H).

The TFA salt of the title compound (4.45 g, 7.78 mmol), prepared by themethod described above using as reagents3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamide,prepared by the method of Preparations 13 and 9, and lithium(45)-2,2-dimethyl-1,3-dioxolane-4-carboxylate, was dissolved in methanol(<10 mL) and diluted with DCM (400 mL). The organic solution was washedwith 1M NaOH (500 mL). The basic aqueous layer was extracted with DCM(2×150 mL). Combined organic layers were washed with saturated aqueoussodium chloride (500 mL). The organic layer was dried over potassiumcarbonate. The solution was filtered and solvent was removed in vacuo togive the title compound (3.09 g, 87% yield) as a glassy solid. (m/z):[M+H]⁺ calcd for C₂₆H₃₉N₃O₂, 458.30; found 458.5. ¹H NMR (300 mHz,d₆-DMSO): 7.81-7.83 (s, 1H), 7.61-7.65 (br s, 1H), 7.55-7.60 (d, 1H),7.30-7.35 (d, 1H), 7.18-7.22 (m, 2H), 4.80-4082 (d, 0.8 H), 4.62-4.65(d, 0.64 H), 4.50-4.60 (m, 1.1 H), 4.22-4.38 (m, 0.83 H), 4.10-4.20 (m,0.65 H), 3.00-3.50 (m, 8H), 2.70-2.99 (m, 2H), 2.00-2.30 (m, 4H),1.60-1.80 (m, 2H), 1.43-1.60 (m, 4H), 1.22-1.40 (m, 3H), 0.93-1.19 (m,3H), 0.82-0.94 (m, 2H).

Example 58B: Synthesis of crystalline3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamidesulfate a. Preparation of N-cyclohexylmethyl-(2-oxoethyl)-carbamic acidbenzyl ester

To a 100 mL flask was added N-cyclohexylmethyl-(2-oxoethyl)-carbamicacid benzyl ester bisulfate adduct (3.94 g, 1 mmol) and MeTHF (35 mL),followed by water (25 mL). The resulting slurry was stirred at roomtemperature for 5 min and 1 M NaOH (8 mL) was added. The reactionmixture was stirred at room temperature for 45 min. The layers wereseparated and the volume of the organic layer was reduced to ˜8 mL toprovide the crude title intermediate.

b. Preparation of2-[3-endo-(3-carbamoylphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}cyclohexylmethyl-carbamicacid benzyl ester

To the product of the previous step was added DMF (15 mL) followed by3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-benzamide hydrochloride (2.67 g, 1mmol), prepared by the process of Preparation 25 and then DMF (10 mL).The mixture was stirred at room temperature for 30 min, cooled to 10° C.and then sodium triacetoxyborohydride (4.25 g, 2 mmol) was added. Thereaction mixture was stirred at room temperature for 90 min and thencooled to 10° C. Isopropyl acetate (100 mL) was added, followed by 1 MNaOH (50 mL). The mixture was stirred for 15 min, and the phases wereseparated. The organic layer was washed with brine in water (1:1, 2×50mL) and the volume of the organic layer was reduced to ˜10 mL to providethe crude title intermediate.

c. Preparation of3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl}benzamide

To the product of the previous step was added EtOH (30 mL) andconcentrated HCl (1.5 mL). The solution was purged with nitrogen, 10%palladium on carbon (470 mg) was added and the mixture was purged withnitrogen for 5 min and then hydrogenated at 30 psi overnight. Afterpurging with nitrogen for 2 min, the solution was filtered throughCelite and solvent was removed to ˜10 mL. Isopropyl acetate (40 mL) and1 M NaOH (20 mL) were added. The layers were separated and the organiclayer was washed with brine (20 mL), phases were separated and organicsolvent removed to 5-10 mL. Isopropyl acetate (20 mL) was added and thevolume reduced to ˜8 mL to which isopropyl acetate (20 mL) was added.The resulting slurry was stirred at room temperature for 2 h. Theproduct was isolated by filtration, the reaction flask and filter cakewere washed with isopropyl acetate (10 mL) to yield the titleintermediate (2.4 g, 98% pure) as an off-white solid.

d. Preparation of3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamidesulfate (hydrate form)

To a 500 mL flask was added3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl}benzamide(31 g, 83.9 mmol) and DMF (150 mL). The mixture was stirred for 10 minand then benzotriazol-1-yloxytris(pyrrolidino)-phosphoniumhexafluoro-phosphate (56.8 g, 109 mmol) and lithium(4S)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (15.6 g, 92.3 mmol) wereadded and the mixture was stirred at room temperature for 2 h. Ethylacetate (600 mL) and 0.5 M NaOH (300 mL) were added and the phases wereseparated. The organic layer contained crude(5)-2,2-dimethyl-[1,3]dioxolane-4-carboxylic acid{2-[3-(3-carbamoyl-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}cyclohexylmethyl-amide(˜84 mmol) which was not isolated.

The organic layer was washed with brine in water (1:1, 2×300 mL) and thephases were separated. To the organic layer was added 2 M H₂SO₄ (42 mL)and the reaction mixture was stirred at room temperature overnight.Acetonitrile (300 mL) was added and the resulting slurry was stirred for2-6 h. The product was isolated by filtration, the filter cake werewashed with acetonitrile (200 mL), dried in air for 2 h and then undervacuum at room temperature for 20 h to provide the title compound (40 g,97% pure by HPLC) as a white powder.

e. Synthesis of crystalline3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamidesulfate

To a 100 mL flask was added3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamidesulfate hydrate form (2 g) and MeOH (40 mL). The resulting slurry washeated to 65° C. under nitrogen for 20 min resulting in completedissolution. The solution was cooled to room temperature with stirring.About 20 mL of solvent was removed under slightly reduced pressure andthe resulting slurry stirred at room temperature overnight. The productwas isolated by filtration, and the flask and filter cake were washedwith acetonitrile (2×5 mL). The filter cake was dried in air for 2 h andthen under vacuum at room temperature overnight to provide the titlecompound (1.71 g, >99% pure by HPLC, ˜85% yield) as a white powder.

A sample prepared according to the above procedure was characterized by¹H NMR (400 MHz, DMSO d₆): δ (ppm) 9.08 & 8.94 (two sets of brs, 1H),7.99-8.04 (m, 2H), 7.74-7.76 (m, 1H), 7.68-7.70 (m, 1H), 7.41-7.45 (m,2H), 4.81, 5.00 and 5.30 (three sets of brs, 2H), 4.34 (deformed m, 1H),4.00 & 4.05 (deformed m, 2H), 3.01-3.25 and 3.47-3.55 and 3.75-3.82(three sets of m, 10H), 2.50-2.55 (m, 2H), 1.99 (deformed m, 2H),1.56-1.70 (m, 8H), 1.15-1.19 (m, 3H), 0.89-0.99 (m, 2H).

Example 58C: Synthesis of crystalline3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamideglycolate

3-endo-(8-{2-[Cyclohexylmethyl-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamide(35 mg) was dissolved in aqueous acetone (2% water, 98% acetone, 0.46mL). To this solution was added 0.78 M glycolic acid in acetonitrile(0.10 mL). A precipitate formed rapidly and over 2 h converted to abirefringent material. The mother liquor was decanted and the remainingsolid was dried to provide the title compound. The x-ray powderdiffraction pattern (XRPD) of the crystalline material is shown inFIG. 1. Diffraction peaks were observed at 2θ values of 8.00±0.2,12.50±0.2, 16.19±0.2, 16.91±0.2, 18.41±0.2, 20.69±0.2, 22.04±0.2,23.03±0.2, 25.44±0.2, 25.85±0.2, and 28.76±0.2.

All XRPD data presented herein was obtained with a Rigaku diffractometerusing Cu Kα (30.0 kV, 15.0 mA) radiation operating in continuous-scanmode of 3° per min with a step size of 0.03°.

Example 58D: Synthesis of crystalline3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamideoxalate

3-endo-(8-{2-[Cyclohexylmethyl-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamide(25.4 mg) was dissolved in acetone (0.34 mL). To this solution was added0.4M oxalic acid in acetonitrile (0.14 mL) followed by water (0.24 mL).The resulting dispersion was sonciated for 30 seconds and then water(0.045 mL) and DCM (0.015 mL) was added. After 4 days, the titlecompound was recovered by vacuum filtration as a crystalline solid (19.8mg). The XRPD of the crystalline material is shown in FIG. 2.Diffraction peaks were observed at 2θ values of 5.84±0.2, 13.80±0.2,17.03±0.2, 23.00±0.2, and 28.85±0.2,

Example 59: Synthesis of3-endo-(8-{2-[(2-hydroxyacetyl)phenethylamino]-ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide

The product of preparation 17 (˜0.26 mmol) was dissolved in DCM (0.5 mL)and cooled to 0° C. The reaction mixture was treated withN,N-diisopropylethylamine (100 mg, 0.78 mmol) and then with acetoxyacetyl chloride (39 mg, 0.29 mmol). The reaction mixture was dilutedwith dichloromethane and washed with saturated sodium bicarbonate andbrine. The organic layer was dried with sodium sulfate, filtered, andconcentrated. The crude oil was dissolved in ethanol (1 mL) and treatedwith lithium hydroxide monohydrate (66 mg, 1.2 mmol) in water (0.5 mL).After an hour, the reaction mixture was concentrated and the residue wasdissolved in 50% acetic acid in water (1.2 mL), filtered, and purifiedby preparative HPLC to give the TFA salt of the title compound (38.7 mg)(m/z): [M+H]⁺ calcd for C₂₆H₃₃N₃O₃, 436.25; found 436.4.

Examples 60-62

Following the procedure of Example 59, substituting the product ofPreparations 18, 19, and 20, respectively for the product of Preparation17, the TFA salts of the compounds of Examples 60-62 were prepared.

Example 60

3-endo-(8-{2-[(2-hydroxyacetyl)-(3-phenylpropyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamide(66.7 mg) (m/z): [M+H]⁺ calcd for C₂₇H₃₅N₃O₃, 450.27; found 450.4.

Example 61

3-endo-(8-{2-[(2-cyclohexylethyl)-(2-hydroxyacetyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamide(68.6 mg) (m/z): [M+H]⁺ calcd for C₂₆H₃₉N₃O₃, 442.30; found 442.6.

Example 62

3-endo-(8-{2-[(3-cyclohexylpropyl)-(2-hydroxyacetyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamide(37.1 mg) (m/z): [M+H]⁺ calcd for C₂₇H₄₁N₃O₃, 456.31; found 456.4.

Example 63A: Synthesis of3-endo-(8-{2-[(4,4-difluorocyclohexylmethyl)-(2-hydroxyacetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide

Following the procedure of Example 48, the product of Preparation 21,3-endo-(8-{2-[(4,4-difluorocyclohexylmethyl)-amino]ethyl}8-azabicyclo[3.2.1]oct-3-yl)benzamide(72.5 mg, 1 eq) was treated with acetoxyacetyl chloride (1.3 eq),hydrolyzed, and purified by HPLC to provide the TFA salt of the titlecompound (14.4 mg). (m/z): [M+H]⁺ calcd for C₂₅H₃₅F₂N₃O₃, 464.27; found464.2.

Example 63B: Synthesis of3-endo-(8-{2-[(4,4-difluorocyclohexylmethyl)-(2-hydroxyacetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide

To a solution of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-benzamide preparedby the method of Preparation 13 (2.15 g, 9.34 mmol) in DCM (45.0 mL) at0° C. was added acetic acid (0.56 g, 9.34 mmol) followed by a solutionof acetic acid[(4,4-difluoro-cyclohexylmethyl)-(2-oxo-ethyl)-carbamoyl]-methyl ester(2.59 g, 8.9 mmol) in DCM (10.0 mL) and sodium triacetoxyborohydride(2.26 g, 10.7 mmol). The resulting mixture was stirred at 0° C. for 30min and then diluted with DCM (40.0 mL). The organic layer was washedsequentially with saturated sodium bicarbonate (20.0 mL) and brine (20.0mL), dried over sodium sulfate, filtered and concentrated to give aceticacid[{2-[3-endo-(3-carbamoyl-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-(4,4-difluoro-cyclohexylmethyl)carbamoyl]methylester as a light yellowish foam.

The product from the previous step was dissolved in methanol (20.0 mL)at ambient temperature and treated with lithium hydroxide monohydrate(0.56 g, 13.4 mmol) in water (5.0 mL) for 30 min. The reaction mixturewas concentrated. The residue was dissolved in 25% acetic acid in water(48.0 mL), filtered and purified by reverse phase preparative HPLC.Desired fractions were combined and freeze dried to give the titlecompound as its TFA salt (2.1 g). ¹H NMR (CD₃OD, 300 MHz) δ (ppm) 8.07(s, 1H), 7.75-7.81 (m, 2H), 7.48-(dd, J=7.8 Hz, 1H), 4.35 (s, 2H), 4.17(brs, 2H), 3.81 (t, J=6.0 Hz, 2H), 3.35-3.38 (obscure, 1H, overlap withsolvent), 3.25 (d, J=6.9 Hz, 2H), 3.20 (t, J=5.4 Hz, 2H), 2.66-2.72 (m,4H), 2.10-2.19 (m, 4H), 1.77-1.90 (m, 7H), 1.33-1.41 (m, 2H).

Example 63C: Synthesis of crystalline3-endo-(8-{2-[(4,4-difluorocyclohexylmethyl)-(2-hydroxyacetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamidephosphate

In a 4 mL glass vial at room temperature,3-endo-(8-{2-[(4,4-difluorocyclohexylmethyl)-(2-hydroxyacetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide(20 mg) was dissolved in methanol (0.172 mL). To this solution was added1.0 M phosphoric acid in methanol (0.043 mL) and acetone (0.228 mL). Themixture was gently stirred for 16 h at room temperature. The titlecompound was recovered by vacuum filtration as a crystalline powder(13.4 mg). The XRPD of the crystalline material is shown in FIG. 3.Diffraction peaks were observed at 2θ values of 5.51±0.20, 7.27±0.20,17.30±0.20, 18.05±0.20, 19.94±0.20, 20.39±0.20, 21.89±0.20, 24.62±0.20,26.66±0.20, 27.38±0.20, 28.52±0.20, 29.21±0.20, and 32.87±0.20.

Examples 64 to 74

A solution of the product of Preparation 22,3-endo-[8-(2-benzylamino-propyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-phenol(509 mg, 1.45 mmol) and N,N-diisopropylethylamine (0.76 mL) indichloromethane (12 mL) was dispensed in 12 equal portions into vialseach containing an appropriate acid chloride (0.16 mmol). The vials wereshaken at room temperature for 45 minutes and then concentrated invacuo. Each residue was dissolved in ethanol (1 mL) and a solution oflithium hydroxide (6 eq.) in water (0.2 mL) was added and the vialsshaken at 40° C. for 30 minutes. The contents of the vials wereconcentrated in vacuo, diluted with acetic acid:water 1:1 (1 mL),filtered and purified by preparative HPLC to afford the TFA salts of thecompounds of Examples 64 to 74.

Example 64

cyclopropanecarboxylic acid(R)-benzyl-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-1-methylethyl}amide(7.9 mg) (m/z): [M+H]⁺ calcd for C₂₇H₃₄N₂O₂, 419.26; found 419.2.

Example 65

N-benzyl-3-cyclopentyl-N-{(R)-2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-1-methylethyl}propionamide(1.9 mg) (m/z): [M+H]⁺ calcd for C₃₁H₄₂N₂O₂, 475.32; found 475.2.

Example 66

N-benzyl-N-{(R)-2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-1-methyl-ethyl}-2-phenylacetamide(3.9 mg) (m/z): [M+H]⁺ calcd for C₃₁H₃₆N₂O₂, 469.28; found 469.2.

Example 67

N-benzyl-N-{(R)-2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-1-methy-ethyl}-3-methylbutyramide(6.5 mg) (m/z): [M+H]⁺ calcd for C₂₈H₃₈N₂O₂, 435.29; found 435.2.

Example 68

N-benzyl-N-{(R)-2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-1-methy-ethyl}-3-methylbutyramide(3.5 mg) (m/z): [M+H]⁺ calcd for C₂₅H₃₂N₂O₃, 409.24; found 409.2.

Example 69

N-benzyl-2-cyclopentyl-N-{(R)-2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-1-methylethyl}acetamide(2.6 mg) (m/z): [M+H]⁺ calcd for C₃₀H₄₀N₂O₂, 461.31; found 461.2.

Example 70

cyclohexanecarboxylic acid(R)-benzyl-{2-[3-endo-(3-hydroxy-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-1-methyl-ethyl}-amide(3.8 mg) (m/z): [M+H]⁺ calcd for C₃₀H₄₀N₂O₂, 461.31; found 461.2.

Example 71

N-benzyl-2-ethyl-N-{(R)-2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-1-methylethyl}butyramide(3.8 mg) (m/z): [M+H]⁺ calcd for C₂₉H₄₀N₂O₂, 449.31; found 449.2.

Example 72

N-benzyl-N-{(R)-2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-1-methylethyl}succinamicacid (5.7 mg) (m/z): [M+H]⁺ calcd for C₂₇H₃₄N₂O₄, 451.25; found 451.2.

Example 73

cyclopentanecarboxylic acid(R)-benzyl-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-1-methylethyl}amide(5.2 mg) (m/z): [M+H]⁺ calcd for C₂₉H₃₈N₂O₂, 447.29; found 447.2.

Example 74

N-benzyl-N-{(R)-2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-1-methylethyl}acetamide(4.6 mg) (m/z): [M+H]⁺ calcd for C₂₅H₃₂N₂O₂, 393.25; found 393.2.

Example 75: Synthesis ofN-cyclohexylmethyl-2-hydroxy-N-{2-[3-endo-(3-methanesulfonylamino-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}acetamidea. Preparation ofcyclohexylmethyl-{2-[3-endo-(3-methanesulfonylamino-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}-carbamicacid tert-butyl ester

To a solution of the TFA salt ofN-[3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-phenyl]-methanesulfonamide, theproduct of Preparation 23 (140 mg, 0.35 mmol) in DCM (2 mL) at roomtemperature was added a solution ofcyclohexylmethyl-(2-oxo-ethyl)carbamic acid tert-butyl ester (116 mg,0.455 mmol) followed by sodium triacetoxyborohydride (96 mg, 0.455mmol). The resulting mixture was stirred at room temperature overnightand then diluted with DCM. The organic layer was washed with saturatedsodium bicarbonate and brine, dried over sodium sulfate, filtered andconcentrated to give the title intermediate as an oily residue, whichwas used directly in the next step. (m/z): [M+H]⁺ calcd for C₂₈H₄₅N₃O₄S:520.31; found: 520.4.

b. Preparation ofN-(3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-phenyl)-methanesulfonamide

The oily product of the previous step was treated with DCM (1.5 mL) andTFA (1.5 mL) at room temperature for thirty minutes. Then it wasconcentrated, redissolved in a 1:1 mixture of acetic acid and water (6mL), filtered and purified by reverse phase preparative HPLC to give thetitle intermediate as its bis TFA salt (38.9 mg). (m/z): [M+H]⁺ calcdfor C₂₃H₃₇N₃O₂S: 420.26; found: 420.4.

c. Synthesis ofN-cyclohexylmethyl-2-hydroxy-N-{2-[3-endo-(3-methanesulfonylamino-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}acetamide

To a solution of the product of the previous step (39 mg, 0.06 mmol) inDCM (0.2 mL) at room temperature was added N,N-diisopropylethylamine (31mg, 0.24 mmol) followed by acetoxyacetylchloride (12 mg, 0.09 mmol).Five minutes later, the reaction was concentrated, redissolved inethanol (0.2 mL) and treated with lithium hydroxide monohydrate (15 mg,0.36 mmol) in water (0.2 mL) at room temperature for thirty minutes. Thereaction mixture was then reconcentrated and the resulting residue wasdissolved in a 1:1 mixture of acetic acid and water (1.5 mL), filteredand purified by reverse phase preparative HPLC to give the titlecompound as its TFA salt (16.9 mg). (m/z): [M+H]⁺ calcd for C₂₅H₃₉N₃O₄S:478.27; found: 478.2.

Examples 76-204

In the following examples, the 8-azabicyclooctane phenol or8-azabicyclooctane benzamide intermediate was prepared according to theprocess of Preparation 13 with the following exceptions: Preparation 1:Example 137; Preparation 12, steps a to c: Examples 106-108 and 112;Preparation 12: Examples 91, 101, 109-111, and 131.

Example 76: Synthesis ofN-cyclohexylmethyl-2-hydroxy-N-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-(S)-phenylacetamide

To a solution of3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}phenol(30 mg, 0.087 mmol) in DMF (0.4 mL) was added HATU (39.6 mg, 0.10 mmol)and (S)-hydroxyphenyl acetic acid (15.2 mg, 0.1 mmol). The reactionmixture was concentrated by rotary evaporation and the residue wasdissolved in 50% acetic acid in water (1.2 mL), filtered, purified bypreparative HPLC to give the title product as a TFA salt (8.6 mg).(m/z): [M+H]⁺ calcd for C₃₀H₄₀N₂O₃ 477.30. found, 477.4.

Examples 77-84

Using processes similar to that of Example 76, except replacing(S)-hydroxy-phenyl-acetic acid with the appropriate carboxylic acid, theTFA salts of the compounds of Examples 77-84 were prepared.

Example 77

(S)—N-cyclohexylmethyl-2-hydroxy-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}-3-phenyl-propionamide(15.9 mg). (m/z): [M+H]⁺ calcd for C₃₁H₄₂N₂O₃, 491.68; found 491.4.

Example 78

(R)—N-cyclohexylmethyl-2-hydroxy-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl-butyramide(17.8 mg). (m/z): [M+H]⁺ calcd for C₃₂H₄₄N₂O₃, 505.34; found 505.4.

Example 79

1-hydroxy-cyclopropanecarboxylic acidcyclohexylmethyl-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}amide(5.7 mg). (m/z): [M+H]⁺ calcd for C₂₆H₃₈N₂O₃, 427.29; found 427.4.

Example 80

(S)-2-hydroxy-4-methyl-pentanoic acidcyclohexylmethyl-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}amide(12.7 mg). (m/z): [M+H]⁺ calcd for C₂₈H₄₄N₂O₃, 457.34; found 457.4.

Example 81

(S)—N-cyclohexylmethyl-2-dimethylamino-N-{2-[3-endo-(3-hydroxy-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-3-phenylpropionamide(9.4 mg). (m/z): [M+H]⁺ calcd for C₃₃H₄₇N₃O₂, 518.37; found 518.6.

Example 82

2-hydroxy-hexanoic acid cyclohexylmethyl-{2-[3-endo(3-hydroxy-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}amide (10.6 mg).(m/z): [M+H]⁺ calcd for C₂₈H₄₄N₂O₃, 457.34; found 457.5.

Example 83

(R)-2-cyclohexyl-N-cyclohexylmethyl-2-hydroxy-N-{2-[3-endo-(3-hydroxy-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}acetamide(9.8 mg). (m/z): [M+H]⁺ calcd for C₃₀H₄₆N₂O₃, 483.35; found 483.2.

Example 84

(S)-2-cyclohexyl-N-cyclohexylmethyl-2-hydroxy-N-{2-[3-endo(3-hydroxy-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}acetamide (14.5mg). (m/z): [M+H]⁺ calcd for C₃₀H₄₆N₂O₃, 483.35; found 483.4.

Examples 85-89

Using processes similar to that of Example 76, replacing theazabicyclooctane phenol with3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamideand utilizing the appropriate carboxylic acid, the TFA salts of thecompounds of Examples 85-89 were prepared.

Example 85

3-endo-(8-{2-[cyclohexylmethyl-((S)-2-hydroxy-3-phenylpropionyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide(15.2 mg). (m/z): [M+H]⁺ calcd for C₃₂H₄₃N₃O₃ 518.33; found, 518.4.

Example 86

3-endo-(8-{2-[cyclohexylmethyl-((S)-2-hydroxy-4-methylpentanoyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide(19 mg). (m/z): [M+H]⁺ calcd for C₂₉H₄₅N₃O₃ 484.35; found, 484.4.

Example 87

3endo-(8-{2-[cyclohexylmethyl-(1-hydroxy-cyclopropanecarbonyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide(15.5 mg). (m/z): [M+H]⁺ calcd for C₂₇H₃₉N₃O₃ 454.30; found, 454.4.

Example 88

3-endo-(8-{2-[cyclohexylmethyl-((S)-2-dimethylamino-3-phenyl-propionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide(17.4 mg). (m/z): [M+H]⁺ calcd for C₃₄H₄₈N₄O₂ 545.38; found, 545.4.

Example 89

3-endo-(8-{2-[cyclohexylmethyl-(3-hydroxy-2,2-dimethyl-propionyl)-amino]-ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide(5.3 mg). (m/z): [M+H]⁺ calcd for C₂₈H₄₃N₃O₃ 470.33; found, 470.4.

Example 90: Synthesis of3-endo-(8-{2-[cyclohexylmethyl-(4-dimethylamino-butyryl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide

To a vial charged with 4-dimethylamino-butyric acid HCl salt (19.7 mg,0.15 mmol) was added DMF (0.3 mL) followed by HATU (57.0 mg, 0.15 mmol).After stirring for 1 h, the reaction mixture was treated with DIPEA(25.8 mg, 0.2 mmol) and3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamidebis TFA salt (30.0 mg, 0.05 mmol). The resulting mixture was stirred atambient temperature for 4 h and then heated at 65° C. overnight. Afterconcentration, the resulting residue was dissolved in 50% acetic acid inwater (1.5 mL) and purified by reverse phase preparative HPLC to givethe title compound as a bis TFA salt (4.9 mg) (m/z): [M+H]⁺ calcd forC₂₉H₄₆N₄O₂ 483.36; found 483.4.

Examples 91-92

Using processes similar to that of Example 90, except replacing4-dimethylamino-butyric acid with the appropriate carboxylic acid, thecompounds of Examples 91-92 were prepared.

Example 91

3-endo-(8-{2-[cyclohexylmethyl-(1-hydroxycyclopropanecarbonyl)-amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (18.8 mg). (m/z): [M+H]⁺ calcd for C₂₇H₃₉N₃O₃ 454.30; found454.2.

Example 92

3-endo-(8-{2-[cyclohexylmethyl-((S)-3-hydroxy-2-methylamino-propionyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamidebis TFA salt (24. mg). (m/z): [M+H]⁺ calcd for C₂₇H₄₂N₄O₃ 471.33; found471.4.

Example 93: Synthesis of3-endo-(8-{2-[cyclohexylmethyl-(3-hydroxy-2-hydroxymethyl-2-methylpropionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamidea. Preparation of 5-methyl-2-phenyl-1,3-dioxinane-5-carboxylic acid

Into a round bottom flask was added sequentially3-hydroxy-2-hydroxymethyl-2-methyl-propionic acid (10.0 g, 74.5 mmol),acetone (75.0 mL), benzaldehyde dimethyl acetal (17.02 g, 111.0 mmol)and para-toluenesulfonic acid monohydrate (0.71 g, 3.7 mmol). Theresulting mixture was stirred at ambient temperature for 4 h and thenfiltered. The filter cake was rinsed with cold acetone and dried undervacuum to give the title compound as a white solid. ¹H NMR (CDCl₃, 300MHz) δ (ppm): 7.46-7.48 (m, 2H), 7.34-7.36 (m, 3H), 5.49 (s, 1H), 4.65(d, J=10.8 Hz, 2H), 3.70 (d, J=11.4 Hz, 2H), 1.11 (s, 3H).

b. Synthesis of3-endo-(8-{2-[cyclohexylmethyl-(3-hydroxy-2-hydroxymethyl-2-methylpropionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide

To a solution of the product of the previous step (55.7 mg, 0.25 mmol)in DMF (0.5 mL) at ambient temperature was added HATU (95.0 mg, 0.25mmol). After stirring for 2 h, the reaction was treated with3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamidebis TFA salt (75.0 mg, 0.13 mmol) followed by DIPEA (64.9 mg, 0.50mmol). The reaction was heated at 40° C. overnight. After concentration,the residue was treated with a mixture of acetic acid (2.1 mL) and water(0.7 mL) at 70° C. for 2 h and then reconcentrated. The resultingresidue was dissolved in 50% acetic acid in water (1.5 mL) and purifiedby reverse phase preparative HPLC to give the TFA salt of the titlecompound (24.6 mg). (m/z): [M+H]⁺ calcd for C₂₈H₄₃N₃O₄ 486.33; found486.4.

Example 94: Synthesis of3-endo-(8-{2-[cyclohexylmethyl-((S)-4-dimethylamino-2-hydroxy-butyryl)-amino]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamidea. Preparation of lithium(S)-4-tert-butoxycarbonylamino-2-hydroxybutyrate

A solution of (S)-4-tert-butoxycarbonylamino-2-hydroxybutyric acidmethyl ester (1.52 g, 6.52 mmol) in methanol (20.0 mL) was treated withlithium hydroxide monohydrate (273.8 mg, 6.52 mmol) and water (2.0 mL)for 30 min, concentrated, and dried under vacuum to give a white solid(1.26 g)

b. Preparation of3-endo-(8-{2-[((S)-4-amino-2-hydroxybutyryl)cyclohexylmethyl-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide

The product of the previous step (150.0 mg, 0.67 mmol) was dissolved inDMF (1.5 mL) at room temperature. To this solution was addedsequentially3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamidebis TFA salt (200.0 mg, 0.335 mmol), HATU (253.3 mg, 0.67 mmol) andDIPEA (173.2 mg, 1.34 mmol). After stirring for 2 h, the reactionmixture was diluted with EtOAc (100.0 mL), washed sequentially with halfsaturated sodium bicarbonate (20.0 mL), saturated sodium bicarbonate(15.0 mL) and brine (15.0 mL), dried over sodium sulfate, filtered, andconcentrated to give the intermediate[(S)-3-(2-[3-(3-endo-carbamoylphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-cyclohexylmethyl-carbamoyl)-3-hydroxy-propyl]-carbamicacid tert-butyl ester as a yellowish oil. (m/z): [M+H]+ calcd forC₃₂H₅₀N₄O₅ 571.4; found 571.6.

The intermediate was then treated with DCM (1.5 mL) and TFA (2.5 mL) atroom temperature for thirty minutes. After concentration, the residuewas dissolved in 25% acetic acid in water (8.0 mL), filtered andpurified by reverse phase preparative HPLC to give the bis TFA salt ofthe title compound (194.4 mg). (m/z): [M+H]⁺ calcd for C₂₇H₄₂N₄O₃ 471.3;found 471.6.

c. Synthesis of3-endo-(8-{2-[((S)-4-dimethylamino-2-hydroxybutyryl)cyclohexylmethyl-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide

To the solution of the product of the previous step (65.3 mg, 0.09 mmol)in methanol (0.3 mL) was added 37% aqueous formaldehyde solution (0.02mL, 0.27 mmol) followed by sodium cyanoborohydride (14.0 mg, 0.27 mmol).The resulting mixture was stirred at room temperature for twenty minutesbefore it was concentrated. The residue was redissolved in 25% aceticacid in water (6.0 mL), filtered and purified by reverse phasepreparative HPLC to give the bis TFA salt of the title compound (33.0mg). ¹H NMR (CD₃OD, 400M Hz) δ (ppm): 8.06 (s, 1H), 7.74-7.81 (m, 2H),7.49-7.51 (m, 1H), 4.66-4.69 (m, 1H), 4.14-4.18 (m, 2H), 3.84-3.89 (m,1H), 3.73-3.78 (m, 1H), 3.37-3.44 (obscure, 3H, partial overlap withsolvent), 3.28-3.30 (obscure 2H, partial overlap with solvent),3.20-3.22 (m, 2H), 2.96 (s, 6H), 2.61-2.70 (m, 4H), 2.09-2.18 (m, 4H),1.74-1.88 (m, 8H), 1.25-1.36 (m, 3H), 1.04-1.12 (m, 2H). (m/z): [M+H]+calcd for C₂₉H₄₆N₄O₃ 499.36; found 499.6.

Example 95: Synthesis of3-endo-(8-{2-[((S)-4-tert-butylamino-2-hydroxy-butyryl)-cyclohexylmethyl-amino]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamide

To a solution of3-endo-(8-{2-[((S)-4-amino-2-hydroxybutyryl)cyclohexylmethyl-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamidebis TFA salt (29.0 mg, 0.04 mmol) in DMF (0.5 mL) was added DIPEA (20.7mg, 0.16 mmol) and tert-butyl iodide (14.7 mg, 0.08 mmol). The resultingmixture was heated at 75° C. for 2 h. After concentration, the residuewas dissolved in 25% acetic acid in water, and purified by reverse phasepreparative HPLC to give the bis TFA salt of the title compound (4.5mg). (m/z): [M+H]⁺ calcd for C₃₁H₅₀N₄O₃ 526.38; found 526.6.

Example 96: Synthesis of3-endo-(8-{2-[cyclohexylmethyl-((S)-4-diethylamino-2-hydroxybutyryl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide

Using a process similar to that of Example 95 replacing tert-butyliodide with ethyl iodide (3.0 eq), the bis TFA salt of the titlecompound was prepared (m/z): [M+H]⁺ calcd for C₃₁H₅₀N₄O₃ 527.39; found527.2.

Example 97: Synthesis of3-endo-(8-{2-[cyclohexylmethyl-(3-dimethylamino-2-hydroxypropionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamidea. Preparation of[2-({2-[3-endo-(3-carbamoylphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}-cyclohexylmethyl-carbamoyl)-2-hydroxy-ethyl]-carbamicacid 9H-fluoren-9-ylmethyl ester

Using a process similar to Example 94 (b) replacing lithium(S)-4-tert-butoxycarbonylamino-2-hydroxy-butyrate with3-(9H-fluoren-9-ylmethoxycarbonylamino)-2-hydroxy-propionic acid (163.7mg, 0.5 mmol, 2.0 eq), the title compound was obtained as a yellowishoil. (m/z): [M+H]⁺ calcd for C₄₁H₅₀N₄O₅ 679.4; found 679.6.

b. Preparation of3-endo-(8-{2-[(3-amino-2-hydroxypropionyl)-cyclohexylmethyl-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide

The product of the previous step was treated with DMF (2.0 mL) andpiperidine (0.4 mL) at ambient temperature for 5 min and thenconcentrated. The residue was purified by reverse phase preparative HPLCto give the bis TFA salt of the title compound (93.7 mg). (m/z): [M+H]⁺calcd for C₂₆H₄₀N₄O₃ 457.3; found 457.4.

c. Synthesis of3-endo-(8-{2-[cyclohexylmethyl-(3-dimethylamino-2-hydroxypropionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide

Following the process of Example 94 c, the bis TFA salt of the titlecompound was prepared (m/z): [M+H]⁺ calcd for C₂₈H₄₄N₄O₃ 485.34; found485.4.

Example 98: Synthesis of3-endo-(8-{2-[cyclohexylmethyl-(4-hydroxy-butyryl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide

To a solution of γ-butyrolactone (170.0 mg, 1.98 mmol) in methanol (0.5mL) was added water (0.2 mL) and lithium hydroxide monohydrate (83 mg,2.0 mmol). The resulting mixture was stirred at room temperatureovernight. After concentration, the residue was dried over the vacuumline to give the intermediate, lithium 4-hydroxybutyrate as a whitesolid. The intermediate (18.3 mg, 0.17 mmol) was added to a mixture of3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamidebis TFA salt (50 mg, 0.083 mmol) and DIPEA (58.3 μL, 0.33 mmol) in DMF(0.4 mL). Then HATU (63.1 mg, 0.17 mmol) was added and the resultingreaction mixture was stirred at room temperature overnight. Afterconcentration, the residue was redissolved in 50% acetic acid in water(6 mL), filtered and purified by preparative HPLC. Desired fractionswere combined and freeze dried to give a white solid. ¹H NMR (CD₃OD, 400MHz) δ (ppm): 8.05 (s, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.74 (d, J=7.6 Hz,1H), 7.51 (dd, J=7.6, 8.0 Hz, 1H), 4.13 (brs, 2H), 3.78 (t, J=5.6 Hz,2H), 3.69 (t, J=6.0 Hz, 2H), 3.31-3.35 (obscure 3H, overlap withsolvent), 3.17 (t, J=5.6 Hz, 2H), 2.43-2.53 (m, 6H), 2.01-2.05 (m, 2H),1.61-1.84 (m, 10H), 1.12-1.26 (m, 3H), 0.89-0.98 (m, 2H). (m/z): [M+H]⁺calcd for C₂₇H₄₁N₃O₃ 456.31; found 456.4.

Examples 99-100

Using processes similar to that of Example 98, replacing γ-butyrolactonewith the appropriate lactone, the compounds of Examples 99-100 wereprepared.

Example 99

3-endo-(8-2-[cyclohexylmethyl-((S)-2,4-dihydroxybutyryl)amino]ethyl-8-azabicyclo[3.2.1]oct-3-yl)benzamideTFA salt, (m/z): [M+H]⁺ calcd for C₂₇H₄₁N₃O₄ 472.31; found 472.4.

Example 100

3-endo-(8-2-[cyclohexylmethyl-((S)-3,4-dihydroxybutyrylamino]ethyl-8-azabicyclo[3.2.1]oct-3-yl)benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₇H₄₁N₃O₄ 472.31; found 472.4.

Example 101 Synthesis of3-endo-(8-{2-[cyclohexylmethyl-(2-dimethylamino-acetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamidea. Preparation of3-endo-{(8-[2-(cyclohexylmethyl-amino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamide

Following the procedure of Preparations 9 and 12,3-endo-(8-aza-bicyclo[3.2.1]oct-3-yl)benzamide (1.18 g) was reacted withcyclohexylmethyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester (1.57 g)to give{2-[3-endo-(3-carbamoylphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}cyclohexylmethyl-carbamicacid tert-butyl ester, which was further treated with DCM and TFA. Theresulting crude product was dissolved in 50% acetic acid in water (15.0mL) and purified by reverse phase preparative HPLC. Desired fractionswere combined and freeze dried to give the bis TFA salt of the titlecompound (1.65 g). ¹H NMR (CD₃OD, 300 MHz) δ (ppm): 8.03 (s, 1H),7.71-7.77 (m, 2H), 7.44-7.50 (m, 1H), 4.11 (brs, 2H), 3.52 (t, J=6.0 Hz,2H), 3.33-3.40 (obscure, 3H, overlap with solvent), 2.96 (d, J=6.6 Hz,2H), 2.67-2.67 (m, 4H), 2.05-2.12 (m, 2H), 1.70-1.84 (m, 8H), 1.20-1.39(m, 3H), 1.03-1.10 (m, 2H). (m/z): [M+H]+ calcd for C₂₃H₃₅N₃O, 370.28;found 370.2.

b. Synthesis of3-endo-(8-{2-[cyclohexylmethyl-(2-dimethylamino-acetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide

To a solution of the product of the previous step (33.0 mg, 0.055 mmol)in DCM (0.3 mL) at ambient temperature was added DIPEA (28.4 mg, 0.22mmol) followed by dimethylamino-acetyl chloride HCl salt (12.6 mg, 0.08mmol). The reaction mixture was stirred for 10 min and thenconcentrated. The resulting residue was dissolved in 50% acetic acid inwater (1.5 mL), filtered and purified by reverse phase preparative HPLCto give the bis TFA salt of the title compound. (16.1 mg). (m/z): [M+H]⁺calcd for C₂₇H₄₂N₄O₂ 455.33; found 455.2.

Examples 102-103

Using processes similar to that of Example 101, replacingdimethylamino-acetyl chloride with the appropriate chloride, thecompounds of Examples 102-103 were prepared.

Example 102

3-endo-(8-(2-((cyclohexylmethyl)(N,N-dimethylsulfamoyl)amino)ethyl)-8-azabicyclo[3.2.1]oct-3-yl)benzamideTFA salt (21.2 mg). (m/z): [M+H]⁺ calcd for C₂₅H₄₀N₄O₃S, 477.28; found477.2.

Example 103

3-endo-(8-{2-[cyclohexylmethyl-(2-methoxyacetyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]+ calcd for C₂₆H₃₉N₃O₃ 442.30; found 442.4.

Example 104: Synthesis of3-endo-(8-{2-[((S)-2,3-dihydroxypropionyl)-(3-hydroxy-adamantan-1-ylmethyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamide a. Preparation of 3-aminomethyl-adamantan-1-ol

To a vigorously stirred mixture of concentrated sulfuric acid (22.7 mL)and 65% nitric acid (2.3 mL) at 0° C. was addedC-adamantan-1-yl-methylamine (2.0 g, 12.12 mmol) dropwise. The reactionmixture was stirred for 2 h at 0° C., warmed to room temperature andstirred at that temperature for 24 h, cooled to 0° C. and slowlyquenched with ice (10.8 g). The mixture was allowed to warm to ambientas ice melts overnight, cooled to 0° C. again and treated with sodiumhydroxide (50 g) in small portions. The resulting brownish paste wasfiltered, and the filter cake was rinsed with DCM (200 mL). Afterseparation, the organic layer was washed with brine (2×20 mL), driedover sodium sulfate, filtered and concentrated to give a white solid(1.09 g). (m/z): [M+H]⁺ calcd for C₁₁H₁₉N, 182.2; found 182.2.

b. Preparation of3-endo-(8-{2-[(3-hydroxy-adamantan-1-ylmethyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide

To a solution of3-endo-[8-(2-oxoethyl)-8-azabicyclo[3.2.1]oct-3-yl)-benzamide HCl salt(108.6 mg, 0.60 mmol) in DCM (5.0 mL) was added sodiumtriacetoxyborohydride (137.8 mg, 0.65 mmol) followed by the product fromthe previous step (190.0 mg, 0.50 mmol). The resulting mixture wasstirred at ambient for 2 h before it was concentrated. The residue wasdissolved in 25% acetic acid in water (6.0 mL), filtered and purified byreverse phase preparative HPLC to give the bis TFA salt of the titlecompound (91.0 mg). (m/z): [M+H]⁺ calcd for C₂₇H₃₉N₃O₂ 438.3; found438.4.

c. Synthesis of3-endo-(8-{2-[((S)-2,3-dihydroxypropionyl)-(3-hydroxy-adamantan-1-ylmethyl)amino]ethyl}-8-aza-bicyclo-[3.2.1]oct-3-yl)benzamide

To a suspension of lithium (4S)-2,2-dimethyl-1,3-dioxolane-4-carboxylate(28.0 mg, 0.17 mmol) in DMF (0.5 mL) was added HATU (62.5 mg, 0.164mmol) at room temperature. The mixture was sonicated to aid dissolving.After 1 h, DIPEA (87.9 mg, 0.68 mmol) was added followed by the productfrom previous step (60.0 mg, 0.085 mmol). The resulting mixture wasstirred for 2 h and then concentrated. The residue was treated with amixture of acetic acid (2.1 mL) and water (0.7 mL) at 70° C. for 1 h.After concentration, the oily residue was dissolved in 50% acetic acidin water (3.0 mL) and purified by reverse phase preparative HPLC to givethe TFA salt of the title compound (6.2 mg). (m/z): [M+H]+ calcd forC₃₀H₄₃N₃O₅ 526.32; found 526.4.

Example 105 Synthesis of3-endo-(8-{2-[(2-hydroxyacetyl)-(3-hydroxy-adamantan-1-ylmethyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamidesalt

To a solution of3-endo-(8-{2-[3-hydroxy-adamantan-1-ylmethyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamidebis TFA salt (132.2 mg, 0.20 mmol) in DCM (1.0 mL) was added DIPEA (0.14mL, 0.79 mmol) followed by acetoxyacetal chloride (54.6 mg, 0.40 mmol)at room temperature. The reaction mixture was stirred for 5 min, andthen concentrated. The resulting residue was redissolved in methanol(2.0 mL) and treated with lithium hydroxide monohydrate (50.0 mg, 1.2mmol) for 30 min and reconcentrated. The residue was dissolved in 50%acetic acid in water (1.5 mL), filtered and purified by reverse phasepreparative HPLC to give the TFA salt of the title compound (23.4 mg).¹H NMR (CD₃OD, 400 MHz) δ (ppm): 8.16 (s, 1H), 7.88 (d, J=7.6 Hz, 1H),7.85 (d, J=8.0 Hz, 1H), 7.60 (dd, J=7.6, 8.0 Hz, 1H), 4.46 & 4.44 (twosets of s, 2H total), 4.25 & 4.20 (two sets of brs, 2H total), 3.92 (t,J=5.6 Hz, 2H), 3.44-3.46 (m, 1H), 3.31 (t, J=5.6 Hz, 2H), 3.25 (s, 2H),2.75-2.82 (m, 4H), 2.36 (brs, 2H), 2.24-2.30 (m, 2H), 1.92-1.98 (m, 2H),1.62-1.85 (m, 12H). (m/z): [M+H]+ calcd for C₂₉H₄₁N₃O₄ 496.31. found496.4.

Examples 106-112

Using processes similar to that of Examples 104b and 105, using theappropriate oxoethyl-8-azabicyclooctane and appropriate chloride, thecompounds of Examples 106-112 were prepared.

Example 106

N-adamantan-1-ylmethyl-2-hydroxy-N-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}acetamideTFA salt (m/z): [M+H]⁺ calcd for C₂₈H₄₀N₂O3 453.31; found 453.2.

Example 107

N-adamantan-1-ylmethyl-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}acetamideTFA salt (m/z): [M+H]⁺ calcd for C₂₈H₄₀N₂O₂ 437.31; found 437.2.

Example 108

N-adamantan-1-ylmethyl-N-{2-[3-endo-3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}succinamicacid TFA salt (m/z): [M+H]⁺ calcd for C₃₀H₄₂N₂O₄ 495.31; found 495.2.

Example 109

3-endo-(8-{2-[adamantan-1-ylmethyl-(2-hydroxyacetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₉H₄₁N₃O3 480.31; found 480.2.

Example 110

N-adamantan-1-ylmethyl-N-{2-[3-endo-(3-carbamoyl-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}succinamicacid TFA salt (m/z): [M+H]⁺ calcd for C₃₁H₄₃N₃O4 522.33; found 522.2.

Example 111

3-endo-{8-[2-(acetyl-adamantan-1-ylmethyl-amino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₉H₄₁N₃O2 464.32; found 464.2.

Example 112

N-(2,6-difluorobenzyl)-N-{2-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}succinamicacid TFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₀F₂N₂O₄ 473.22; found 473.2.

Example 113: Synthesis ofN-(2,6-Difluoro-benzyl)-N-{2-[3-(3-hydroxy-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-succinamicacid 3-endo-(8-{2-[(2,6-difluorobenzyl)-(2-hydroxy-acetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamidea. Preparation of 2-(2,6-difluorobenzylamino)ethanol

A mixture of 2,6-difluorobenzyl bromide (3.7 g, 17.8 mmol) andethanolamine (6.46 mL, 107 mmol) in ethanol (18 mL) was heated at 75° C.for 16 h. The reaction mixture was concentrated and the resultingresidue was diluted with dichloromethane (50 mL). The organic layer waspartitioned with water (75 mL) and the aqueous layer extracted withdichloromethane (50 mL). Combined organic layers were dried overmagnesium sulfate, filtered, and concentrated to give the title compoundas a yellow solid (3.25 g). (m/z): [M+H]⁺ calcd for C₉H₁₁F₂NO, 188.08;found, 188.1. ¹H NMR (d₆-DMSO, 300 MHz) δ (ppm): 7.37-7.34 (m, 1H),7.10-7.05 (m, 2H), 4.47 (t, J=5.4 Hz, 1H), 3.75 (s, 2H), 3.42 (q, J=5.5Hz, 2H), 2.25 (t, J=5.7 Hz, 2H), 1.82 (br s, 1H).

b. Preparation of (2,6-difluorobenzyl)-(2-hydroxyethyl)-carbamic acidtert-butyl ester

To the solution of the product of the previous step (3.25 g, 17.4 mmol)in dichloromethane (20 mL) at 0° C. was added a solution ofdi-tert-butyl dicarbonate (3.40 g, 15.6 mmol) via a syringe dropwiseover 5 min. The resulting mixture was slowly warmed to room temperatureand stirred overnight under an atmosphere of nitrogen. The crudereaction mixture was diluted with DCM (50 mL) and washed successivelywith 1 N aq HCl (2×50 mL), saturated NaHCO₃ (3×50 mL) and brine (50 mL).The organic layer was dried with magnesium sulfate, filtered, andconcentrated to yield the title compound (4.46 g). (m/z): [M+H]⁺ calcdfor C₁₄H₁₉F₂NO₃, 288.13; found, 288.2.

c. Preparation of (2,6-difluoro-benzyl)-(2-oxo-ethyl)-carbamic acidtert-butyl ester

To the solution of the product of the previous step (4.46 g, 15.5 mmol)in DCM (50 mL) at 0° C. was added sequentially dimethyl sulfoxide (1.79g, 23 mmol), DIPEA (5.01 g, 38.9 mmol) and sulfur trioxide pyridiumcomplex (6.20 g, 38.9 mmol). After 30 min, the reaction was washedsuccessively with 1N aq HCl (3×100 mL), saturated NaHCO₃ (100 mL) andbrine (100 mL), filtered, and eluted with DCM. After concentration, thetitle compound was obtained as a yellow oil (2.31 g). ¹H NMR (d₆-DMSO,300 MHz) δ (ppm): 9.42 (s, 1H), 7.40 (m, 1H), 7.09 (m, 2H), 4.49 (s,2H), 4.00 (d, J=24.6, 2H), 1.31 (s, 9H).

d. Preparation of{2-[3-endo-(3-carbamoylphenyl)-8-azabicyclo[3.2.1]oct-3-yl]-ethyl}-(2,6-difluorobenzyl)-carbamicacid tert-butyl ester

To a solution of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)benzamide (120 mg,0.56 mmol) in DCM (2 mL) at 0° C. was added a solution of the product ofthe previous step (193 mg, 0.68 mmol) in DCM (1 mL) followed by sodiumtriacetoxyborohydride (144 mg, 0.68 mmol). The resulting mixture waswarmed to room temperature and allowed to react for 1 h. The reactionmixture was diluted with DCM, washed with saturated sodium bicarbonateand brine, dried over sodium sulfate, filtered, and concentrated to givea yellowish oil and used in next step without further purification.(m/z): [M+H]⁺ calcd for C₂₈H₃₅F₂N₃O₃, 500.26; found, 500.1.

e. Preparation of: 3-endo-{8-[2-(2,6-difluorobenzylamino)ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-benzamide

The oily residue from the previous step was dissolved in DCM (2 mL) andtreated with TFA (2 mL) at room temperature for 2 h. The mixture wasconcentrated and coevaporated with ethyl acetate three times, dilutedwith DCM and basified to pH=8.0 with saturated sodium bicarbonate. Thelayers were separated and the aqueous layer was extracted with DCM. Thecombined organic layer was washed with brine, dried over sodium sulfate,filtered, and concentrated to yield a dark oil (200 mg). (m/z): [M+H]⁺calcd for C₂₃H₂₇F₂N₃O, 400.21; found, 400.4.

f. Synthesis of3-endo-(8-{2-[(2,6-difluorobenzyl)-(2-hydroxyacetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide

To a solution of the mono-TFA salt of3-endo-{8-[2-(2,6-difluorobenzylamino)-ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamide(132 mg, 0.26 mmol) in DCM (1 mL) at 0° C. was added DIPEA (132 mg, 1.0mmol). The reaction mixture was then treated with acetoxy acetylchloride (46 mg, 0.34 mmol) for 30 min. The reaction mixture wasconcentrated and the crude oil was dissolved in ethanol (0.5 mL) andtreated with lithium hydroxide monohydrate (66 mg, 1.65 mmol) in water(0.2 mL). The solvent was concentrated and the residue was dissolved in50% acetic acid in water (5 mL), filtered, and purified by preparativeHPLC to give the TFA salt of the title compound (30.8 mg). (m/z): [M+H]⁺calcd for C₂₅H₂₉F₂N₃O₃, 458.22; found, 458.2. ¹H NMR (CD₃OD, 400 MHz) δ(ppm): 8.025 (s, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H),7.49-7.45 (m, 2H), 7.103 (t, J=8.8 Hz, 2H), 4.67 (s, 2H), 4.52 (s, 2H),4.10 (br s, 2H), 3.71 (t, J=6.0 Hz, 2H), 3.4-3.3 (obscure, 1H, overlapwith solvent), 3.08 (t, J=5.6, 2H), 2.63-2.61 (m, 4H), 2.06-2.03 (m,2H), 1.83-1.79 (m, 2H).

Examples 114-118

Using processes similar to that of Example 113 (f), utilizing theappropriate chloride, the compounds of Examples 114-118 were prepared.

Example 114

3-endo-(8-(2-((2,6-difluorobenzyl)(N,N-dimethylsulfamoyl)amino)ethyl)-8-azabicyclo[3.2.1]oct-3-yl)benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₅H₃₂F₂N₄O₃S, 507.22; found, 507.4.

Example 115

3-endo-(8-{2-[(2,6-difluorobenzyl)-(2-hydroxy-2-methylpropionyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₇H₃₃F₂N₃O₃, 486.25; found, 486.4.

Example 116

3-endo-(8-{2-[(2,6-difluorobenzyl)-(2-methoxyacetyl)-amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₁F₂N₃O₃, 472.23; found, 472.4. ¹HNMR (CD₃OD, 400 MHz) δ (ppm): 8.023 (s, 1H), 7.75 (d, J=8.0 Hz, 1H),7.72 (d, J=8.8 Hz, 1H) 7.49-7.45 (m, 2H), 7.103 (t, J=8.4 Hz, 2H), 4.72(s, 2H), 4.45 (s, 2H), 4.08 (br s, 2H), 3.71 (t, J=6.0 Hz, 2H), 3.48 (s,3H), 3.4-3.3 (obscure, 1H, overlap with solvent), 3.05 (t, J=5.6, 2H),2.62-2.59 (m, 4H), 2.05-2.02 (m, 2H), 1.81-1.79 (m, 2H).

Example 117

3-endo-(8-{2-[(2,6-difluorobenzyl)-(2,2-dimethylpropionyl)amino]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₈H₃₅F₂N₃O₂, 484.27; found, 484.4.

Example 118

3-endo-(8-{2-[(2,6-difluorobenzyl)-methanesulfonylamino]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₄H₂₉F₂N₃O₂S, 478.19; found, 478.2; ¹HNMR (CD₃OD, 400 MHz) δ (ppm): 8.00 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.70(d, J=8.4 Hz, 1H) 7.49-7.45 (m, 2H), 7.10 (t, J=8.4 Hz, 2H), 4.67 (s,2H), 4.10 (br s, 2H), 3.65 (t, J=6.0 Hz, 2H), 3.4-3.3 (obscure, 1H,overlap with solvent), 3.10 (t, J=5.6 Hz, 2H), 2.99 (s, 3H), 2.62-2.59(m, 4H), 2.04-2.02 (m, 2H), 1.83-1.81 (m, 2H).

Example 119: Synthesis of3-endo-(8-{2-[(2,6-difluorobenzyl)-(2-methanesulfonylacetyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamide

To a solution of methanesulfonyl-acetic acid (80.8 mg, 0.58 mmol) in DMF(1.0 mL) was added HATU (220 mg, 0.58 mmol). After stirring for 1 h atroom temperature, the reaction mixture was treated with the mono-TFAsalt of3-endo-{8-[2-(2,6-difluorobenzylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamide(150 mg, 0.29 mmol) and DIPEA (74.8 mg, 0.58 mmol) at 45° C. for 16 h.The solvent was concentrated and the residue dissolved in 50% aceticacid in water (5 mL), filtered, and purified by preparative HPLC to givethe TFA salt of the title compound (52.4 mg). (m/z): [M+H]⁺ calcd forC₂₆H₃₁F₂N₃O₄S, 520.20; found, 520.4; ¹H NMR (CD₃OD, 400 MHz) δ (ppm):8.01 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H) 7.51-7.45(m, 2H), 7.11 (t, J=8.4 Hz, 2H), 4.89 (s, 2H), 4.68 (s, 2H), 4.10 (br s,2H), 3.78 (t, J=6.0 Hz, 2H), 3.4-3.3 (obscure, 1H, overlap withsolvent), 3.26 (s, 3H), 3.15 (t, J=5.6 Hz, 2H), 2.63-2.60 (m, 4H),2.09-2.06 (m, 2H), 1.83-1.80 (m, 2H).

Examples 120-129

Using processes similar to that of Example 119, utilizing theappropriate carboxylic acid or carboxylate, the compounds of Examples120-129 were prepared.

Example 120

3-endo-(8-{2-[(2,6-difluorobenzyl)-((S)-2-hydroxy-3-phenylpropionyl)-amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamideTFA salt (m/z): [M+H]⁺ calcd for C₃₂H₃₅F₂N₃O₃, 548.26; found, 548.4.

Example 121

3-endo-(8-{2-[(2,6-difluorobenzyl)-((S)-2-hydroxy-4-methylpentanoyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₉H₃₇F₂N₃O₃ 514.28; found, 514.4.

Example 122

3-endo-(8-{2-[(2,6-difluoro-benzyl)-((R)-2,3-dihydroxypropionyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₁F₂N₃O₄, 488.23; found, 488.4.

Example 123

3-endo-(8-{2-[(2,6-difluorobenzyl)-((S)-2,3-dihydroxypropionyl)-amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₁F₂N₃O₄, 488.23; found, 488.2.

Example 124

3-endo-(8-{2-[(2,6-difluorobenzyl)-((S)-2-hydroxypropionyl)amino]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₁F₂N₃O₃, 472.23; found, 472.4; ¹HNMR (CD₃OD, 400 MHz) δ (ppm): 8.02 (s, 1H), 7.77-7.70 (m, 2H), 7.50-7.45(m, 2H), 7.10 (t, J=8.0 Hz, 2H), 4.91 (s, 2H), 4.08-4.00 (m, 2H),3.87-3.83 (m, 1H), 3.61-3.60 (m, 1H), 3.01 (t, J=6.0 Hz, 2H), 2.63-2.61(m, 4H), 2.04-1.99 (m, 2H), 1.81-1.79 (m, 2H), 1.40 (d, J=6.4 Hz, 3H).

Example 125

3-endo-(8-{2-[(2,6-difluorobenzyl)-(3-hydroxy-2,2-dimethylpropionyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₈H₃₅F₂N₃O₃, 500.26; found, 500.4; ¹HNMR (CD₃OD, 400 MHz) δ (ppm): 8.01 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.70(d, J=7.6 Hz, 1H), 7.49 (m, 2H), 7.09 (t, J=8.4 Hz, 2H), 5.02 (s, 2H),4.04 (br s, 2H), 3.78 (s, 2H), 3.66 (t, J=6.4 Hz, 2H), 3.4-3.3 (obscure,1H, overlap with solvent), 2.98 (t, J=6.0 Hz, 2H), 2.66-2.54 (m, 4H),2.02-1.99 (m, 2H), 1.80-1.76 (m, 2H), 1.41 (s, 6H). Reagentlithium-3-hydroxy-2,2-dimethyl-propionic carboxylate prepared bytreating 3-hydroxy-2,2-dimethyl-propionic acid methyl ester (5.0 g, 37.7mmol) in methanol (45 mL) with lithium hydroxide monohydrate (1.6 g,37.8 mmol).

Example 126

3-endo-(8-{2-[(2-cyanoacetyl)-(2,6-difluorobenzyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₂₈F₂N₄O₂ 467.22; found, 467.2; ¹HNMR (CD₃OD, 400 MHz) δ (ppm): 8.02 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.72(d, J=7.6 Hz, 1H), 7.50-7.48 (m, 2H), 7.12 (t, J=8.4 Hz, 2H), 4.72 (s,2H), 4.11 (br s, 2H), 3.70 (t, J=6.4 Hz, 2H), 3.4-3.3 (obscure, 1H,overlap with solvent), 3.09 (t, J=6 Hz, 2H), 2.65-2.59 (m, 4H),2.06-2.05 (m, 2H), 1.82-1.79 (m, 2H).

Example 127

3-endo-(8-{2-[(2,6-difluorobenzyl)-(1-hydroxycyclopropanecarbonyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamideTFA salt (m/z) [M+H]⁺ calcd for C₂₇H₃₁F₂N₃O₃ 484.23; found, 484.4.

Example 128

3-endo-(8-{2-[(2-tert-butoxyacetyl)-(2,6-difluorobenzyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamideTFAsalt (m/z): [M+H]⁺ calcd for C₂₉H₃₇F₂N₃O₃ 514.28; found, 514.4.

Example 129

3-endo-(8-{2-[(2,6-difluorobenzyl)-(trans-4-hydroxy-cyclohexanecarbonyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamideTFA salt (m/z): [M+H]⁺ calcd for C₃₀H₃₇F₂N₃O₃ 526.28; found, 526.4.

Example 130 Synthesis of3-endo-(8-{3-[cyclohexylmethyl-(2-hydroxy-acetyl)amino]propyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamidea. Preparation of3-endo-[8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]oct-3-yl]-benzamide

A mixture of 3-(8-azabicyclo[3.2.1]oct-3-yl)benzamide (326.7 mg, 1.42mmol) and 3-bromo-1-propanol (217.1 mg, 1.56 mmol) in EtOH (1.0 mL) washeated at 70° C. for one hour. After concentration, the residue wascoevaporated with DCM three times and dried under vacuum to give thetitle compound as a light yellowish foam. (m/z): [M+H]⁺ calcd forC₁₇H₂₄N₂O₂ 289.2; found 289.0.

b. Preparation of methanesulfonic acid3-endo-[3-(3-carbamoyl-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]propyl ester

The product of the previous step was dissolved in DCM (7.0 mL). To theresulting solution was added DIPEA (367.1 mg, 2.84 mmol) followed bymethanesulfonyl chloride (275.2 mg, 2.41 mmol) and DMAP (24.2 mg, 0.20mmol). The reaction was stirred at room temperature for 3 h and thenstored at 4° C. overnight. The reaction mixture was concentrated and theoily residue was dried under vacuum line to give an orange color oilwhich was used directly in the next step.

c.3-endo-{8-[3-(cyclohexylmethylamino)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-benzamide

Half of the crude product of the previous step was dissolved in DMF (0.8mL) and treated with DIPEA (183.2 mg, 1.42 mmol) and cyclohexylmethylamine (200.6 mg, 1.77 mmol) at 75° C. for 1 h. After concentration, theresidue was dissolved in 50% acetic acid in water (8.0 mL), filtered andpurified by reverse phase preparative HPLC to give the title compound asits bis TFA salt (103.9 mg). (m/z): [M+H]⁺ calcd for C₂₄H₃₇N₃O, 384.3;found 384.4.

d. Synthesis of3-endo-(8-{3-[cyclohexylmethyl-(2-hydroxy-acetyl)amino]propyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide

To a solution of the product of the previous step (100.0 mg, 0.164 mmol)in DCM (0.6 mL) was added DIPEA (84.4 mg, 0.65 mmol) followed byacetoxyacetyl chloride (24.5 mg, 0.18 mmol). Five min later, thereaction was concentrated. The residue was redissolved in methanol (0.6mL) and treated with lithium hydroxide monohydrate (41.32 mg, 0.984mmol) in water (0.6 mL) for thirty minutes. The reaction mixture wasconcentrated and the resulting residue was dissolved in a mixture of 50%acetic acid in water (6.0 mL) and water (2.0 mL), filtered and purifiedby reverse phase preparative HPLC to give the title compound as its TFAsalt (22.1 mg). (m/z): [M+H]⁺ calcd for C₂₆H₃₉N₃O3 442.30; found 442.6;¹H NMR (CD₃OD, 400M Hz) δ (ppm): 8.08 (s, 1H), 7.76-7.80 (m, 2H),7.48-7.55 (m, 6H), 4.28 (s, 2H), 4.08 (brs, 2H), 3.36-3.38 (obscure 1H,partially overlap with solvent), 3.20 (t, J=7.2 Hz, 2H), 3.12 (t, J=8.4Hz, 2H), 2.62-2.78 (m, 4H), 2.21-2.29 (m, 2H), 2.09-2.12 (m, 2H),1.78-1.84 (m, 2H).

Example 131 Synthesis of3-endo-{8-[3-(acetylcyclohexylmethylamino)-propyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamide

To a solution of3-endo-{8-[3-(cyclohexylmethylamino)-propyl]-8-aza-bicyclo[3.2.1]oct-3-yl}benzamidebis TFA salt (30.0 mg, 0.05 mmol) in DCM (0.2 mL) was added DIPEA (25.8mg, 0.20 mmol) followed by acetic anhydride (7.65 mg, 0.075 mmol).Thirty minutes later, the reaction was concentrated. The residue wasdissolved in ethanol (0.4 mL) and treated with lithium hydroxidemonohydrate (12.6 mg, 0.30 mmol) in water (0.4 mL) for thirty minutes.The reaction mixture was concentrated and the resulting residue wasdissolved in 50% acetic acid in water (1.5 mL), filtered and purified byreverse phase preparative HPLC to give the title compound as its TFAsalt (26.7 mg). (m/z): [M+H]⁺ calcd for C₂₆H₃₉N₃O₂ 426.30; found 426.2.

Example 132 Synthesis of3-endo-(8-{3-[cyclohexylmethyl-(2-methanesulfonyl-acetyl)amino]propyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide

To a solution of methanesulfonyl acetic acid (20.7 mg, 0.15 mmol) in DMF(0.2 mL) was added N,N-carbonyl diimidazole (24.3 mg, 0.15 mmol) at roomtemperature. Thirty minutes later, to the stirred mixture was addedDIPEA (25.8 mg, 0.20 mmol) and3-endo-{8-[3-(cyclohexylmethylamino)-propyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-benzamidebis TFA (30.0 mg, 0.05 mmol). The resulting reaction mixture was thenheated at 65° C. for 3 h, concentrated, dissolved in 50% acetic acid inwater (1.5 mL), filtered and purified by reverse phase preparative HPLCto give title compound as its TFA salt (16.0 mg). (m/z): [M+H]⁺ calcdfor C₂₇H₄₁N₃O₄S, 504.28; found 504.2.

Example 133: Synthesis of3-endo-(8-{3-[benzyl-(2-hydroxyacetyl)amino]-propyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide

Using the process of Example 130,3-endo-[8-(3-benzylaminopropyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-benzamidebis TFA salt (100 mg, 0.165 mmol) was reacted with acetoxyacetylchloride (24.5 mg, 0.18 mmol) to provide the TFA salt of the titlecompound (22.6 mg). ¹H NMR (CD₃OD, 400M Hz) δ (ppm): 8.08 (s, 1H),7.77-7.81 (m, 2H), 7.51 (t, J=7.6, 8.0 Hz, 1H), 7.31-7.46 (m, 5H),(m/z): [M+H]⁺ calcd for C₂₆H₃₃N₃O₃ 436.25; found 436.4.

Example 134: Synthesis of3-endo-(8-{3-[benzyl-((S)-2-hydroxypropionyl)-amino]propyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamidea. Preparation of benzyl-(3-hydroxypropyl)-carbamic acid tert-butylester

To a mixture of 3-benzylamino-1-propanol HCl salt (2.0 g, 9.9 mmol) inDCM (49.0 mL) at 0° C. was added DIPEA (1.72 mL, 9.9 mmol) followed by asolution of di-tert-butyldicarbonate (1.94 g, 8.91 mmol) in DCM (20.0mL). After being stirred for 3 h at 0° C., the reaction mixture waswashed sequentially with 1N HCl (2×10.0 mL), saturated sodiumbicarbonate (10.0 mL) and brine (10.0 mL), dried over sodium sulfate,filtered, and concentrated to give a yellowish oil (2.22 g). ¹H NMR(CDCl₃, 300 MHz) δ (ppm): 7.20-7.39 (m, 5H), 4.40 (s, 2H), 3.55 (brs,2H), 3.38 (brs, 2H), 1.61 (brs, 2H), 1.44 (s, 9H).

b. Preparation of benzyl-(3-oxo-propyl)-carbamic acid tert-butyl ester

To the solution of the product of the previous step (2.22 g, 7.38 mmol)in DCM (37.0 mL) at 0° C. was added DIPEA (2.38 g, 18.45 mmol) followedby DMSO (0.86 g, 11.07 mmol) and pyridine sulfur trioxide complex (2.93g, 18.45 mmol). After being stirred for 30 min at 0° C., the reactionmixture was diluted with DCM (20.0 mL) and washed sequentially with 1NHCl (10.0 mL), saturated sodium bicarbonate (10.0 mL) and brine (10.0mL), dried over sodium sulfate, filtered and concentrated to give ayellowish oil which was further purified by normal phase chromatographyto give the title compound as a colorless oil (1.54 g). ¹H NMR (CDCl₃,300M Hz) δ (ppm): 9.73 (s, 1H), 7.24-7.36 (m, 5H), 4.45 (s, 2H), 3.51(brs, 2H), 2.65 (brs, 2H), 1.46 (s, 9H).

c. Preparation of3-endo-[8-(3-benzylamino-propyl)-8-azabicyclo[3.2.1]oct-3-yl]-benzamide

To a solution of the product from previous step (972.6 mg, 3.25 mmol) inDCM (16.0 mL) at room temperature was added3-(8-azabicyclo[3.2.1]oct-3-yl)-benzamide (747.5 mg, 3.25 mmol) followedby sodium triacetoxyborohydride (826.6 mg, 3.9 mmol). The resultingmixture was stirred at room temperature for 30 min before it was dilutedwith DCM (40.0 mL). The organic layer was washed with saturated sodiumbicarbonate (20.0 mL) followed by brine (20.0 mL), dried over sodiumsulfate, filtered and concentrated to give a yellowish oil. The oilyresidue was treated with a mixture of TFA (5.0 mL) and DCM (5.0 mL) atroom temperature for 30 min. Then it was concentrated and the resultingresidue was dissolved in a mixture of water (4.0 mL) and acetonitrile(3.0 mL), filtered and purified by reverse phase preparative HPLC togive the title compound as its bis TFA salt (1.22 g). ¹H NMR (CD₃OD, 400MHz) δ (ppm): 8.06 (s, 1H), 7.74-7.78 (m, 2H), 7.46-7.53 (m, 6H), 4.27(s, 2H), 4.08 (br s, 2H), 3.35-3.38 (obscure 1H, partially overlap withsolvent), 3.20 (t, J=8.0 Hz, 2H), 3.12 (t, J=8.4 Hz, 2H), 2.62-2.78 (m,4H), 2.21-2.29 (m, 2H), 2.09-2.12 (m, 2H), 1.79-1.84 (m, 2H). (m/z):[M+H]+ calcd for C₂₄H₃₁N₃O, 378.25; found 378.4.

d. Synthesis of3-endo-(8-{3-[benzyl-((S)-2-hydroxy-propionyl)amino]propyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamide

To a solution of the product of the previous step (30.0 mg, 0.06 mmol)in DCM (0.5 mL) was added DIPEA (32.4 mg, 0.24 mmol) followed byacetoxyacetyl chloride (9.8 mg, 0.072 mmol) at room temperature. Thereaction completed instantly. After concentration, the resulting residuewas redissolved in methanol (0.5 mL) and treated with lithium hydroxidemonohydrate (15.1 mg, 0.36 mmol) for overnight. The reaction wasconcentrated and the residue was dissolved in 50% acetic acid in water(1.5 mL), filtered and purified by reverse phase prep HPLC to give thetitle compound as its TFA salt (23.4 mg). (m/z): [M+H]⁺ calcd forC₂₇H₃₅N₃O₃ 450.27; found 450.4.

Examples 135-199

Using processes described in the above examples, the followingadditional compounds were prepared by reaction of the correspondingintermediate of formula (II) with a suitable acid chloride, carboxylicacid or carboxylate reagent as depicted in Scheme A (i), followed inspecific instances by an N-alkylation step. The intermediates of formula(II) were prepared by reaction of an aldehyde of formula (IV) with anazabicyclooctyl benzamide according to the process of Example 134 (c),as depicted in Scheme B. The aldehydes of formula (IV) were preparedusing the general process depicted in Scheme F, as described, forexample, in Example 134 (a) and (b).

Example 135

3-endo-(8-{2-[((S)-2,3-dihydroxypropionyl)phenethylamino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₇H₃₅N₃O₄ 466.27; found 466.4.

Example 136

3-endo-(8-{2-[(2-methanesulfonylacetyl)phenethylamino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₇H₃₅N₃O₄S, 498.23; found 498.4.

Example 137

acetic acid(benzyl-{2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}carbamoyl)methylester TFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₂N₂O₄ 437.24; found 437.4.

Example 138

3-endo-(8-{2-[benzyl-((S)-2,3-dihydroxypropionyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamideTFA salt ¹H NMR (CD₃OD, 400 MHz) δ (ppm): 8.05 (s, 1H), 7.79 (d, J=7.6Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.37-7.52 (m, 6H), 4.90-4.95 (m, 1H),4.77-4.83 (m, 1H), 4.72 (t, J=5.2 Hz, 1H), 4.10 (brs, 2H), 3.85-3.91 (m,3H), 3.63-3.69 (m, 1H), 3.31-3.34 (obscure 1H, partially overlap withsolvent), 3.09-3.12 (m, 2H), 2.64 (brs, 4H), 2.04-2.07 (m, 2H),1.80-1.83 (m, 2H); (m/z): [M+H]⁺ calcd for C₂₆H₃₃N₃O₄ 452.25; found452.2.

Example 139

3-endo-(8-{3-[benzyl-((S)-2,3-dihydroxypropionyl)amino]propyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]+ calcd for C₂₇H₃₅N₃O₄ 466.26; found 466.4.

Example 140

3-endo-(8-{3-[benzyl-((R)-2,3-dihydroxypropionyl)amino]propyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₇H₃₅N₃O₄ 466.26; found 466.4.

Example 141

3-endo-(8-{3-[benzyl-(2,3-dihydroxybutyryl)amino]propyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₈H₃₇N₃O₄ 480.28; found 480.4.

Example 142

3-endo-(8-{3-[benzyl-(2-methanesulfonylacetyl)amino]propyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt ¹H NMR (CD₃OD, 400 MHz) δ (ppm): 8.04 (s, 1H), 7.72-7.77 (m,2H), 7.48 (t, J=7.6 Hz, 1H), 7.31-7.37 (m, 5H), 4.79 (s, 2H), 4.49 (s,2H), 3.99&3.92 (two sets of brs, 2H), 3.61 (t, J=6.4 Hz, 2H), 3.34-3.38(m, 1H), 3.22 (s, 3H), 2.98 (t, J=8.0 Hz, 2H), 2.53-2.72 (m, 4H),1.96-2.11 (m, 4H), 1.74-1.80 (m, 2H). (m/z): [M+H]⁺ calcd forC₂₇H₃₅N₃O₄S, 498.23; found 498.2.

Example 143

3-endo-(8-{3-[benzyl-(2-hydroxy2-methylpropionyl)amino]-propyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₈H₃₇N₃O₃ 464.28; found 464.4.

Example 144

3-endo-(8-{3-[benzyl-(2,2-dimethylpropionyl)amino]propyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₉H₃₉N₃O₂ 462.30; found 462.4.

Examples 145

3-endo-(8-{2-[(4,4-difluoro-cyclohexylmethyl)-(3-hydroxy-2-hydroxymethyl-2-methylpropionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₈H₄₁F₂N₃O₄ 522.31. found 522.2.

Example 146

3-endo-(8-{2-[(4,4-difluorocyclohexylmethyl)-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₇F₂N₃O₄ 494.28; found 494.4.

Example 147

3-endo-(8-{2-[(4,4-difluorocyclohexylmethyl)-((R)-2,3-dihydroxy-propionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₇F₂N₃O₄ 494.28; found 494.4.

Example 148

3-endo-(8-{2-[(4,4-difluorocyclohexylmethyl)-(2-methanesulfonylacetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt ¹H NMR (CD₃OD, 400 MHz) δ (ppm): 8.06 (s, 1H), 7.79 (d, J=7.6Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.51 (dd, J=7.6, 8.0 Hz, 1H), 4.51 (s,2H), 4.18 (deformed m, 2H), 3.89 (t, J=6.0 Hz, 2H), 3.48 (d, J=7.2 Hz,2H), 3.28 (s, 3H), 3.24 (t, J=6.0 Hz, 2H), 2.65-2.68 (m, 4H), 2.10-2.19(m, 4H), 1.75-1.90 (m, 7H), 1.36-1.45 (m, 2H). (m/z): [M+H]⁺ calcd forC₂₆H₃₇F₂N₃O₄S, 526.25; found 526.4.

Example 149

3-endo-(8-{2-[(4,4-difluorocyclohexylmethyl)-((S)-4-dimethylamino-2-hydroxybutyryl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamidebis TFA salt (m/z): [M+H]+ calcd for C₂₉H₄₄F₂N₄O₃ 535.34; found 535.4.

Example 150

3-endo-(8-2-[(4,4-difluorocyclohexylmethyl)-((S)-2-hydroxypropionyl)-amino]ethyl-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt ¹H NMR (CD₃OD, 400 MHz) δ (ppm): 8.05 (s, 1H), 7.78 (d, J=7.6Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.49 (dd, J=7.6 Hz, 1H), 4.64 (q, J=6.0Hz, 1H), 4.10-4.14 (m, 2H), 3.72-3.86 (m, 1H), 3.32-3.46 (obscure m, 3H,partially overlap with solvent), 3.18 (t, J=5.6 Hz, 2H), 2.64-2.67 (m,4H), 2.11-2.16 (m, 4H), 1.78-1.88 (m, 7H), 1.37-1.43 (m, 5H); (m/z):[M+H]⁺ calcd for C₂₆H₃₇F₂N₃O₃ 478.28; found 478.4.

Example 151

3-endo-(8-{2-[(4-fluorocyclohexylmethyl)-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₈FN₃O₄ 476.28; found 476.4.

Example 152

3-endo-(8-{2-[(4-fluorocyclohexylmethyl)-(2-hydroxyacetyl)amino]-ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₅H₃₆FN₃O₃ 446.27; found 446.4.

Example 153

3-endo-(8-{2-[cyclopentylmethyl-(3-hydroxy-2-hydroxymethyl-2-methyl-propionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₇H₄₁N₃O₄ 472.31; found 472.4.

Example 154

3-endo-(8-{2-[cyclopentylmethyl-((S)-2,3-dihydroxypropionyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₅H₃₇N₃O₄ 444.28; found 444.4.

Example 155

3-endo-(8-{2-[cyclopentylmethyl-((R)-2,3-dihydroxypropionyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₅H₃₇N₃O₄ 444.28; found 444.4.

Example 156

3-endo-(8-{2-[cyclopentylmethyl-(2-methanesulfonylacetyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₅H₃₇N₃O₄S, 476.25; found 476.2.

Example 157

3-endo-(8-{2-[cyclopentylmethyl-(2-hydroxyacetyl)amino]-ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide(m/z): [M+H]+ calcd for C₂₄H₃₅N₃O₃ 414.27; found 414.4.

Example 158

3-endo-(8-{2-[cyclobutylmethyl-(3-hydroxy-2-hydroxymethyl-2-methyl-propionyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₉N₃O₄ 458.29; found 458.4.

Example 159

3-endo-(8-{2-[cyclobutylmethyl-((S)-2,3-dihydroxypropionyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₄H₃₅N₃O₄ 430.26; found 430.4.

Example 160

3-endo-(8-{2-[cyclobutylmethyl-((R)-2,3-dihydroxypropionyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₄H₃₅N₃O₄ 430.26; found 430.4.

Example 161

3-endo-(8-{2-[cyclobutylmethyl-(2-methanesulfonylacetyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₄H₃₅N₃O₄S, 462.23; found 462.2.

Example 162

3-endo-(8-{2-[cyclobutylmethyl-(2-methanesulfonyl-2-methyl-propionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₉N₃O₄S, 490.27; found 490.2.

Example 163

3-endo-(8-{2-[cyclobutylmethyl-(2-hydroxyacetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₃H₃₃N₃O₃ 400.25; found 400.4.

Example 164

3-endo-(8-{2-[cyclobutylmethyl-((S)-2-hydroxypropionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₄H₃₅N₃O₃ 414.27; found 414.4.

Example 165

3-endo-(8-{2-[benzyl-(2-methanesulfonylacetyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₃N₃O₄S, 484.22; found, 484.2; ¹HNMR (CD₃OD, 400 MHz) δ (ppm): 8.01 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.70(d, J=8.0 Hz, 1H), 7.49-7.35 (m, 6H), 4.80 (s, 2H), 4.57 (s, 2H) 4.07(br s, 2H), 3.80 (t, J=6.0 Hz, 2H), 3.4-3.3 (obscure, 1H, overlap withsolvent), 3.25 (s, 3H), 3.08 (t, J=6 Hz, 2H), 2.61-2.60 (m, 4H),2.03-2.00 (m, 2H), 1.82-1.79 (m, 2H).

Example 166

3-endo-(8-{2-[benzyl-(2-hydroxy-2-methylpropionyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₇H₃₅N₃O₃, 450.27; found, 450.2.

Example 167

3-endo-(8-{2-[benzyl-((S)-2-hydroxy-1-oxopropyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₃N₃O₃, 436.25; found, 436.5; ¹HNMR (CD₃OD, 400 MHz) δ (ppm): 8.02 (s, 1H), 7.77-7.70 (m, 2H), 7.50-7.32(m, 6H), 4.83-4.71 (m, 2H), 4.07-4.01 (m, 2H), 3.81 (m, 1H), 3.64 (m,1H), 3.03 (t, J=6.0 Hz, 2H), 2.63-2.60 (m, 4H), 2.03-1.94 (m, 2H),1.80-1.77 (m, 2H), 1.40 (d, J=6.4 Hz, 3H).

Example 168

3-endo-(8-{2-[benzyl-(2,2-dimethylpropionyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₈H₃₇N₃O₂, 448.29; found, 448.

Example 169

3-endo-{8-[2-(benzyl-methanesulfonylamino)ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₄H₃₁N₃O₃S, 442.21; found, 442.2.

Example 170

3-endo-(8-{2-[benzyl-(2-methoxyacetyl)-amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₃N₃O₃, 436.25; found, 436.5.

Example 171

3-endo-(8-{2-[benzyl-(3-hydroxy-2,2-dimethylpropionyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₈H₃₇N₃O₃, 464.28; found, 464.2.

Example 172

3-endo-(8-{2-[benzyl-(1-hydroxy-cyclopropanecarbonyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₇H₃₃N₃O₃, 448.25; found, 448.3.

Example 173

3-endo-(8-{2-[benzyl-(2-cyanoacetyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₀N₄O₂, 431.24; found, 431.5.

Example 174

3-endo-(8-{2-[benzyl-((R)-3-hydroxy-2-(S)-hydroxybutyryl)amino]-ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₇H₃₅N₃O₄, 466.26; found, 466.4.

Example 175

3-endo-(8-{2-[benzyl-((R)-2,3-dihydroxypropionyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₃N₃O₄, 452.25; found, 452.2.

Example 176

3-endo-(8-{2-[cyclopentylmethyl-(3-hydroxypropionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₅H₃₇N₃O₃, 428.28; found, 428.4.

Example 177

3-endo-(8-{2-[cyclopentylmethyl-(3-hydroxy-2,2-dimethylpropionyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₇H₄₁N₃O₃, 456.31; found, 456.5.

Example 178

3-endo-(8-{2-[cyclopentylmethyl-(trans-4-hydroxycyclohexanecarbonyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₉H₄₃N₃O₃, 482.33; found, 482.5.

Example 179

3-endo-(8-{2-[cyclopentylmethyl-(2,2-dimethylpropionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₇H₄₁N₃O, 440.32; found, 440.4.

Example 180

3-endo-{8-[2-(cyclopentylmethyl-methanesulfonylamino)ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₃H₃₅N₃O₃S, 434.24; found, 434.2.

Example 181

3-endo-(8-{2-[(2-hydroxyacetyl)-(4-trifluoromethylbenzyl)-amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₀F₃N₃O₃, 490.22; found, 490.4.

Example 182

3-endo-(8-(2-((4-trifluoromethylbenzyl)(N,N-dimethylsulfamoyl)amino-ethyl)-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₃F₃N₄O₃S, 539.22; found, 539.5.

Example 183

3-endo-(8-{2-[(2-methanesulfonylacetyl)-(4-trifluoromethyl-benzyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₇H₃₂F₃N₃O₄S, 552.21; found, 552.4; ¹HNMR (CD₃OD, 400 MHz) δ (ppm): 8.02 (s, 1H), 7.77-7.70 (m, 4H), 7.56-7.54(m, 3H)) 4.94 (s, 2H), 4.56 (s, 2H), 4.12 (br s, 2H), 3.80 (t, J=5.6 Hz,2H), 3.4-3.3 (obscure, 1H, overlap with solvent), 3.26 (s, 3H), 3.17 (t,J=5.6 Hz, 2H), 2.63-2.61 (m, 4H), 2.10-2.06 (m, 2H), 1.84-1.81 (m, 2H).

Example 184

3-endo-(8-{2-[(4-fluorobenzyl)-(2-methanesulfonylacetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₂FN₃O₄S, 502.21; found, 502.4; ¹HNMR (CD₃OD, 400 MHz) δ (ppm): 8.01 (s, 1H), 7.77-7.68 (m, 2H), 7.46 (t,J=8.0 Hz, 1H), 7.40-7.36 (m, 2H), 7.15 (t, J=8.8 Hz, 2H), 4.79 (s, 2H)4.10 (br s, 2H), 3.78 (t, J=6.0 Hz, 2H), 3.4-3.3 (obscure, 1H, overlapwith solvent), 3.25 (s, 3H), 3.11 (t, J=5.6 Hz, 2H), 2.61-2.60 (m, 4H),2.06-2.03 (m, 2H), 1.80-1.78 (m, 2H).

Example 185

3-endo-(8-{2-[(4-fluorobenzyl)-(2-hydroxyacetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt ((m/z): [M+H]⁺ calcd for C₂₅H₃₀FN₃O₃, 440.23; found, 440.4.

Example 186

3-endo-(8-(2-((4-fluoromethylbenzyl)(N,N-dimethylsulfamoyl)-amino)ethyl)-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₅H₃₃FN₄O₃S, 489.23; found, 489.5.

Example 187

3-endo-(8-{2-[[2-(3-fluorophenyl)ethyl]-(2-hydroxyacetyl)amino]-ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₂FN₃O₃, 454.24; found, 454.2.

Example 188

3-endo-(8-{2-[[2-(4-fluorophenyl)ethyl]-(2-hydroxyacetyl)amino]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₂FN₃O₃, 454.24; found, 454.4; ¹HNMR (CD₃OD, 400 MHz) δ (ppm): 8.03 (s, 1H), 7.77-7.71 (m, 2H), 7.47 (t,J=8.0 Hz, 1H), 7.30-7.26 (m, 2H), 7.08-7.04 (m, 2H), 4.13 (br s, 2H)4.08 (s, 2H), 3.78 (t, J=5.2 Hz, 2H), 3.52 (t, J=7.2 Hz, 2H), 3.4-3.3(obscure, 1H, overlap with solvent), 3.17 (t, J=5.6 Hz, 2H), 2.91 (t,J=7.6 Hz, 2H), 2.65-2.61 (m, 4H), 2.14-2.11 (m, 2H), 1.85-1.82 (m, 2H).

Example 189

3-endo-(8-{2-[[2-(4-fluorophenyl)ethyl]-(2-methanesulfonyl-acetyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₇H₃₄F₂N₃O₄S, 516.23; found, 516.4; ¹HNMR (CD₃OD, 400 MHz) δ (ppm): 8.01 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.70(d, J=8.0 Hz, 1H) 7.49-7.45 (m, 1H), 7.32 (m, 2H), 7.08 (m, 2H), 4.21(s, 2H), 4.11 (br s, 2H), 3.79-3.73 (m, 2H), 3.4-3.3 (obscure, 1H,overlap with solvent), 3.19 (s, 3H), 3.16 (t, J=5.6 Hz, 2H), 2.97 (t,J=7.2 Hz, 2H), 2.63-2.60 (m, 4H), 2.12-2.09 (m, 2H), 1.83-1.80 (m, 2H).

Example 190

3-endo-[8-(2-{(2-hydroxyacetyl)-[2-(4-hydroxyphenyl)ethyl]-amino}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₃N₃O₄, 452.25; found, 452.2.

Example 191

3-endo-(8-{2-[[2-(4-hydroxyphenyl)ethyl]-(2-methanesulfonyl-acetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₇H₃₅N₃O₅S, 514.23; found, 514.3.

Example 192

3-endo-(8-{2-[(3-fluorobenzyl)-(2-hydroxyacetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₅H₃₀FN₃O₃, 440.23; found, 440.4; ¹HNMR (CD3OD, 400 MHz) δ (ppm): 8.03 (s, 1H), 7.77-7.71 (m, 2H), 7.49-7.43(m, 2H), 7.13-7.06 (m, 3H), 4.62 (s, 2H), 4.37 (s, 2H) 4.12 (br s, 2H),3.75 (t, J=5.6 Hz, 2H), 3.4-3.3 (obscure, 1H, overlap with solvent),3.12 (t, J=5.6 Hz, 2H), 2.64-2.62 (m, 4H), 2.09-2.06 (m, 2H), 1.84-1.81(m, 2H)

Example 193

3-endo-(8-{2-[(3-fluorobenzyl)-(2-methanesulfonyl-acetyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₂FN₃O₄S, 502.21; found, 502.4; ¹HNMR (CD₃OD, 400 MHz) δ (ppm): 8.02 (s, 1H), 7.77-7.70 (m, 2H), 7.49-7.45(m, 2H), 7.19-7.11 (m, 3H), 4.8-4.9 (obscure, 2H, overlap with solvent),4.56 (s, 2H) 4.10 (br s, 2H), 3.80 (t, J=5.6 Hz, 2H), 3.4-3.3 (obscure,1H, overlap with solvent), 3.25 (s, 3H), 3.13 (t, J=6.0 Hz, 2H),2.63-2.60 (m, 4H), 2.08-2.05 (m, 2H), 1.83-1.80 (m, 2H).

Example 194

3-endo-(8-{2-[(2,2-difluoro-2-phenylethyl)-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₇H₃₃F₂N₃O₄, 502.24; found, 502.4.

Example 195

3-endo-(8-{2-[(2-methanesulfonylacetyl)-(4-methyl-cyclohexylmethyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₇H₄₁N₃O₄S, 504.28; found, 504.4.

Example 196

3-endo-(8-{2-[((S)-2,3-dihydroxypropionyl)-(4-methyl-cyclohexyl-methyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₇H₄₁N₃O₄, 472.31; found, 472.4.

Example 197

3-endo-(8-{2-[(2-hydroxy-acetyl)(4-trifluoromethyl-cyclohexyl-methyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₆H₃₆F₃N₃O₃, 496.27; found, 496.4.

Example 198

3-endo-(8-{2-[(2-methanesulfonylacetyl)-(4-trifluoromethyl-cyclohexyl-methyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₇H₃₈F₃N₃O₄S, 558.25; found, 558.4.

Example 199

3-endo-8-{2-[((S)-2,3-dihydroxypropionyl)-(4-trifluoromethyl-cyclohexylmethyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamideTFA salt (m/z): [M+H]⁺ calcd for C₂₇H₃₈F₃N₃O₄, 526.28; found, 526.4.

Example 200: Synthesis of3-endo-(8-{2-[cyclohexylmethyl-((R)-2,3-dihydroxy-propionyl)-amino]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamidea. Preparation of lithium (R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate

To a solution of (R)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid methylester (5.0 g, 31.25 mmol) in MeOH (32.0 mL) at room temperature wasadded a solution of lithium hydroxide monohydrate (1.31 g, 31.25 mmol)in water (10.0 mL). The resulting mixture was stirred for thirty minbefore it was concentrated. The resulting white solid was further driedunder vacuum to give the title compound (4.59 g).

b. Preparation of (R)-2,2-dimethyl-[1,3]dioxolane-4-carboxylic acid{2-[3-endo-(3-carbamoyl-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}cyclohexylmethyl-amide

3-endo-{8-[2-(Cyclohexylmethylamino)-ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-benzamide(600 mg, 1.6 mmol) was dissolved in DMF (5 mL) and lithium(R)-2,2-dimethyl-[1,3]dioxolane-4-carboxylate (270 mg, 1.78 mmol) wasadded as a solid. The solution was stirred at room temperature until thesolid dissolved, then HATU (687 mg, 1.78 mmol) was added as a solid. Thebright yellow solution was stirred at room temperature overnight. Thereaction was diluted with ethyl acetate (100 mL). The organic solutionwas washed with saturated aqueous sodium bicarbonate and saturatedaqueous sodium chloride. The organic solution was dried over anhydroussodium sulfate and solvent was removed in vacuo to yield the titlecompound (781 mg) as a crude yellow oil.

c. Synthesis of3-endo-(8-{2-[cyclohexylmethyl-((R)-2,3-dihydroxy-propionyl)-amino]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamide

The crude product of the previous step was dissolved in acetonitrile (10mL) and 1N HCl (aqueous) (10 mL) was added. The yellow solution wasstirred at room temperature for 2 h; then the reaction was concentratedunder vacuum. The crude material was dissolved in acetonitrile/water/TFAand purified by preparative HPLC to give the TFA salt of the titlecompound as a white powder (386 mg, 99.4% pure). (m/z): [M+H]⁺ calcd forC₂₆H₃₉N₃O₄ 458.30; found, 458.4.

Example 201: Synthesis of3-endo-(8-{2-[(2-hydroxyacetyl)-(2,2,3,3-tetramethyl-cyclopropylmethyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamidea. Preparation of (2,2,3,3-tetramethyl-cyclopropyl)methanol

To a stirred solution of 2,2,3,3-tetramethylcyclopetanecarboxylic acid(500 mg, 3.5 mmol) in THF (25 mL) was added 2.0 M borane dimethylsulfidecomplex in THF (1.8 mL, 3.5 mmol) at 0° C. The reaction mixture waswarmed and stirred at 50° C. for 3 h. The solution was cooled to roomtemperature and methanol (10 mL) was carefully added. The reactionmixture was concentrated and filtered. The filtrate was concentrated togive the title intermediate as an oil (250 mg, 56%). ¹H NMR (CDCl₃, 300MHz) δ (ppm): 4.16 (t, J=4.8 Hz, 1H), 3.39 (dd, J=4.5, 7.5 Hz, 2H), 1.03(s, 6H), 0.93 (s, 6H), 0.38 (t, J=7.5 Hz, 1H).

b. Preparation of 2,2,3,3-tetramethyl-cyclopropanecarbaldehyde

To a stirred solution of the product of the previous step and DIPEA (680μL, 4.0 mmol) in DCM (5 mL) was added a solution of sulfurtrioxide-pyridine complex (620 mg, 3.9 mmol) in DMSO (5 mL) at −20° C.After 2 h, the reaction was warmed to room temperature, diluted with DCM(20 mL) and washed with 1.0 N HCl (25 mL) and water (25 mL). Theorganics were separated, dried with anhydrous sodium sulfate, filtered,and concentrated. The crude material was purified by silica gelchromatography to give the title intermediate (45 mg, 18%).

c. Preparation of (2-hydroxyethyl)-carbamic acid benzyl ester

To a stirred solution of ethanolamine (4.0 g, 66 mmol) in DCM (4 mL) wasadded benzyl chloroformate (4.6 mL, 33 mmol) at 0° C. After 1 h, thereaction mixture was warmed to room temperature and washed with 1.0N HCl(40 mL) and water (40 mL). The organics were separated, dried withanhydrous sodium sulfate, filtered, and concentrated. To a solution ofthe crude product in ethyl acetate (30 mL) was added hexanes (30 mL).The resulting crystals were filtered and dried to give the titleintermediate as a white solid (4.5 g, 70%). ¹H NMR (CDCl₃, 300 MHz) δ(ppm): 7.4-7.29 (m, 5H), 5.00 (s, 2H), 4.64 (t, J=5.5 Hz, 1H), 3.38 (q,J=6.0 Hz, 2H), 3.07 (t, J=6.0 Hz, 2H).

d. Preparation of (2-oxo-ethyl)-carbamic acid benzyl ester

To a stirred solution of (2-hydroxyethyl)carbamic acid benzyl ester (1.0g, 5.1 mmol) and DIPEA (1.78 mL, 10.2 mmol) in DCM (15 mL) was added asolution of sulfur trioxide-pyridine complex (1.63 g, 10.2 mmol) in DMSO(15 mL) at −20° C. After 1 h, the reaction was warmed to roomtemperature, diluted with dichloromethane (50 mL) and washed with 1.0 NHCl (50 mL) and brine. The organics were separated, dried with anhydroussodium sulfate, filtered, concentrated, and purified by silica gelchromatography to give the title intermediate (810 mg, 82%). ¹H NMR(CDCl₃, 300 MHz) δ (ppm): 9.5 (s, 1H) 7.4-7.2 (m, 5H), 5.1 (s, 2H), 3.9(d, J=5.8 Hz, 2H), 2.9-3.3 (br, 1H).

e. Preparation of{2-[3-endo-(3-carbamoylphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-carbamicacid benzyl ester

A suspension of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-benzamide and(2-oxo-ethyl)carbamic acid benzyl ester (0.99 g, 6.2 mmol) in DCM (20mL) was sonicated for 5 min. To the stirred suspension was added sodiumtriacetoxyborohydride (1.3 g, 6.1 mmol). After stirring for 30 min, thereaction mixture was concentrated. The crude reaction mixture wasdiluted with ethyl acetate (50 mL) and washed with 1.0N NaOH (50 mL) andwater (50 mL). The organics were separated, dried with anhydrous sodiumsulfate, filtered, concentrated and purified by silica gelchromatography to provide the title intermediate (1.4 g, 57%). (m/z):[M+H]⁺ calcd for C₂₄H₂₉N₃O₃, 408.22; found 408.5.

f. Preparation of3-endo-[8-(2-aminoethyl)-8-azabicyclo[3.2.1]oct-3-yl]-benzamide

A solution of the product of the previous step (1.4 g, 3.4 mmol) inmethanol (20 mL) was added to palladium hydroxide on carbon (50 wt %water, 20% Pd on dry base, 140 mg). The reaction mixture was stirredunder an atmosphere of hydrogen overnight. The solution was filteredthrough celite and concentrated to give an oil (1.0 g), which was useddirectly in the next step. (m/z): [M+H]⁺ calcd for C₁₆H₂₃N₃O, 274.19.found 274.5.

g. Preparation of3-endo-(8-{2-[(2,2,3,3-tetramethyl-cyclopropylmethyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide

To a solution of the product of the previous step (100 mg, 0.37 mmol)and the product of step b (45 mg, 0.37 mmol) in dichloromethane (2 mL)and methanol (0.2 mL) was added sodium triacetoxyborohydride (93 mg,0.44 mmol). After stirring for 1 h, the reaction mixture wasconcentrated. The crude reaction mixture was diluted with ethyl acetate(20 mL) and washed with 1.0 N NaOH (20 mL). The organics were separated,dried with anhydrous sodium sulfate, filtered, and concentrated. Thecrude product was used directly in the next step. (m/z): [M+H]⁺ calcdfor C₂₄H₃₇N₃O, 384.30; found 384.3.

h Synthesis of3-endo-(8-{2-[(2-hydroxyacetyl)-(2,2,3,3-tetramethyl-cyclopropylmethyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide

To a solution of the product of the previous step (0.366 mmol) in DCM (2mL) was added acetoxyacetyl chloride (50 μL, 0.44 mmol). After 1 h, thereaction mixture was concentrated and the resulting crude oil wasstirred in methanol (2.0 mL) and 6.0 N NaOH (35 μL) overnight. Thereaction mixture was concentrated and purified by preparative HPLC togive the TFA salt of the title compound (30.9 mg). (m/z): [M+H]⁺ calcdfor C₂₆H₃₉N₃O₃, 442.30; found 442.4.

Examples 202-203

Intermediates for Examples 202 and 203 were prepared as follows:

To a solution of 4-hydroxycyclohexanecarboxylic acid ethyl ester as amixture of cis and trans isomers (8.7 g, 50.51 mmol) in THF (300 mL) at0° C. was added imidazole (4.8 g, 70.72 mmol), DMAP (20 mol %, 1.23 g,10.10 mmol,) and tert-butyl dimethylchlorosilane (9.1 g, 60.61 mmol).The reaction mixture was warmed to room temperature, stirred overnight,and diluted with ethyl acetate and saturated aqueous ammonium chloride.The aqueous layer was extracted with ethyl acetate and the combinedorganic layers were washed with brine and dried over sodium sulfate.Solvent was removed and the crude oil was filtered through silica geland solvent removed to give4-(tert-butyldimethylsilanyloxy)cyclohexanecarboxylic acid ethyl ester(11.1 g, 77%) as a mixture of diastereomers.

To a solution of the product of the previous step (11.1 g, 38.7 mmol) inMTBE (150 mL) and methanol (2.35 mL, 58.11 mmol) was added lithiumborohydride (1.27 g, 58.11 mmol). The reaction mixture was heated to 50°C. for 2 h, cooled to room temperature and quenched with methanol. Thesolution was diluted with ethyl acetate, washed with saturated aqueoussodium bicarbonate and brine, and dried over magnesium sulfate. Solventwas removed in vacuo to give crude[4-(tert-butyldimethylsilanyloxy)cyclohexyl]methanol as a mixture ofdiastereomers. Crude material was purified via silica gel chromatography(10-40% ethyl acetate/hexanes) to separate cis and trans diastereomers.Top spot (cis isomer)¹H NMR (300 mHz, CD₃OD): 3.91-3.95 (m, 1H),3.31-3.32 (d, 2H), 1.61-1.63 (m, 2H), 1.36-1.46 (m, 7H), 0.85-0.86 (s,9H), 0.00 (s, 6H). Bottom spot (trans isomer)¹H NMR data (300 mHz,CD₃OD): 3.49-3.53 (m, 1H), 3.27-3.28 (d, 2H), 1.81-1.84 (m, 2H),1.71-1.74 (m, 2H), 1.28-1.36 (m, 1H), 1.18-1.26 (m, 2H), 0.93-0.97 (m,2H), 0.82-0.84 (s, 9H), 0.00 (s, 6H).

Example 202: Synthesis of3-endo-(8-{2-[(trans-4-hydroxycyclohexylmethyl)-((S)-2,3-dihydroxypropionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamidea. Preparation of toluene-4-sulfonic acidtrans-4-(tert-butyldimethylsilanyloxy)-cyclohexylmethyl ester

To a solution oftrans-[4-(tert-butyldimethylsilanyloxy)cyclohexyl]methanol (555 mg, 2.24mmol) in DCM (20 mL) at 0° C. was added DIPEA (0.59 mL, 3.37 mmol), DMAP(20 mol %, 54 mg), and p-toluene-sulfonyl chloride (570 mg, 2.68 mmol).The reaction mixture was stirred at room temperature for 2 h, DABCO (250mg) was added. The reaction mixture was stirred overnight. The solutionwas diluted with DCM, washed with saturated aqueous sodium bicarbonateand brine, and dried over sodium sulfate. Solvent was removed in vacuoto give the title intermediate. ¹H NMR (300 mHz, CD₃OD): 7.75-7.77 (d,2H), 7.40-7.42 (d, 2H), 3.80-3.81 (d, 1H), 3.45-3.51 (m, 1H), 2.40 (s,3H) 1.78-1.82 (m, 2H), 1.62-1.71 (m, 2H), 1.48-1.58 (m, 1H), 1.30-1.33(m, 1H), 1.15-1.21 (m, 2H), 0.85-1.00 (m, 2H), 0.85-0.90 (s, 9H), 0.00(s, 6H).

b. Preparation of2-{[trans-4-(tert-butyldimethylsilanyloxy)cyclohexylmethyl]amino}-ethanol

To a solution of toluene-4-sulfonic acidtrans-4-(tert-butyldimethylsilanyloxy)-cyclohexylmethyl ester (600 mg,1.50 mmol) in acetonitrile (15 mL) was added ethanolamine (2.0 mL, 25eq). The solution was heated to 50° C. overnight. The reaction wasdiluted with DCM (200 mL), washed with saturated aqueous sodiumbicarbonate and brine, and dried over potassium carbonate. Solvent wasremoved to give crude title intermediate (0.44 g) as a yellow oil.(m/z): [M+H]⁺ calcd for C₁₅H₃₃NSiO₂, 288.3; found 288.2.

c. Preparation of [trans-4-(tert-butyldimethylsilanyloxy)cyclohexylmethyl]-(2-hydroxy-ethyl)-carbamic acid tert-butyl ester

To a solution of the product of the previous step (0.44 g, 1.50 mmol) inDCM (30 mL) was added di-tert-butyl dicarbonate (324 mg, 1.48 mmol). Thereaction mixture was stirred at room temperature for 2 h, diluted withDCM (100 mL), washed with saturated aqueous sodium bicarbonate andbrine, and dried over potassium carbonate. Solvent was removed to givethe title intermediate (0.496 g) as a yellow oil.

d. Preparation of[trans-4-(tert-butyldimethylsilanyloxy)cyclohexylmethyl]-(2-oxo-ethyl)carbamicacid tert-butyl ester

To a solution of the product of the previous step (496 mg, 1.27 mmol) inDCM (20 mL) at −15° C. was added DMSO (12.7 mmol, 0.905 mL) and DIPEA(1.103 mL, 6.35 mmol). The reaction was stirred for 10 min, andpyridine.sulfur trioxide complex (1.01 g, 6.35 mmol) was added. Thereaction mixture was stirred for 1 h, warmed to room temperature,diluted with DCM (50 mL), washed with saturated aqueous sodiumbicarbonate and brine, and dried over sodium sulfate. Solvent wasremoved in vacuo to give the title intermediate (480 mg) as a yellowoil.

e. Preparation of [trans-4-(tert-butyldimethylsilanyloxy)cyclohexylmethyl]-{2-[3-endo-(3-carbamoylphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}carbamicacid tert-butyl ester

To a solution of the product of the previous step (480 mg, 1.24 mmol) inDCM (20 mL) was added 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-benzamide(343 mg, 1.48 mmol). The reaction mixture was stirred for 30 min, thensodium triacetoxyborohydride (525 mg, 2.48 mmol) was added. The reactionmixture was stirred for 2 h at room temperature, diluted with DCM (100mL), washed with saturated aqueous sodium bicarbonate and brine, anddried over sodium sulfate. Solvent was removed in vacuo to give crudetitle intermediate (700 mg, 94%) as a crunchy yellow solid. (m/z):[M+H]⁺ calcd for C₃₄H₅₈N₃SiO₄, 600.4; found 600.6.

f. Preparation of 3-endo-(8-{2-1(trans-4-hydroxycyclohexylmethyl)aminol-ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide

The product of the previous step (700 mg, 1.16 mmol) was dissolved inDCM (15 mL) and trifluoroacetic acid was added (7 mL). The reactionmixture was stirred for 2 h at room temperature and then diluted withDCM (100 mL) and 1N NaOH (100 mL). The aqueous layer was extracted withdichloromethane (2×25 mL) and combined organic layers were washed withbrine and dried over sodium sulfate. Solvent was removed in vacuo togive crude title intermediate (425 mg, 94% yield). (m/z): [M+H]⁺ calcdfor C₂₃H₃₆N₃O₂, 386.3; found 386.5.

g. Preparation of (S)-2,2-dimethyl-[1,3]dioxolane-4-carboxylic acid{2-[3-endo-(3-carbamoyl-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-(trans-4-hydroxy-cyclohexylmethyl)amide

To a solution of the product of the previous step (425 mg, 1.10 mmol) inDMF (15 mL) was added lithium(S)-2,2-dimethyl-[1,3]dioxolane-4-carboxylate (0.19 g., 1.21 mmol) andHATU (0.46 g, 1.21 mmol). The reaction mixture was stirred at roomtemperature overnight, diluted with DCM (100 mL), washed with water, 1:1water:saturated aqueous sodium bicarbonate, and brine, then dried overpotassium carbonate. Solvent was removed in vacuo to give crude titledintermediate as a yellow oil. (m/z): [M+H]⁺ calcd for C₂₉H₄₃N₃O₅, 514.3;found 514.5.

h. Synthesis of3-endo-(8-{2-[(trans-4-hydroxycyclohexylmethyl)-((S)-2,3-dihydroxypropionyl)amino]ethyl}-8-azabicyclo[13.2.1]oct-3-yl)-benzamide

The product of the previous step was dissolved in acetonitrile (15 mL)and 1N HCl (15 mL) and the solution was stirred at room temperature for2 h. The reaction mixture was diluted with DCM (200 mL) and 1N NaOH (150mL). The aqueous layer was extracted with dichloromethane (2×50 mL) andcombined organic layers were washed with brine and dried over sodiumsulfate. Solvent was removed in vacuo and the crude material waspurified by preparative HPLC to give the TFA salt of the title compound(45 mg) as a white powder. (m/z): [M+H]⁺ calcd for C₂₆H₃₉N₂O₅, 474.29.found 474.4. ¹H NMR (300 mHz, CD₃OD): 8.00-8.02 (s, 1H), 7.65-7.80 (m,2H), 7.40-7.45 (t, 1H), 4.59-4.62 (m, 1H), 3.95-4.20 (m, 3H) 3.65-3.79(m, 2H), 3.40-3.60 (m, 2H), 3.10-3.20 (m, 2H), 2.05-2.19 (m, 2H),1.95-2.00 (m, 2H), 1.40-1.85 (m, 4H), 1.20-1.35 (m, 2H), 1.01-1.20 (m,2H).

Example 203: Synthesis of3-endo-(8-{2-[(cis-4-hydroxycyclohexylmethyl)-((S)-2,3-dihydroxypropionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide

Following the procedure of Example 202, using the corresponding cisisomer, cis-[4-(tert-butyldimethylsilanyloxy)cyclohexyl]methanol in stepa, the title compound was prepared. (m/z): [M+H]⁺ calcd for C₂₆H₃₉N₂O₅,474.29; found 474.4. ¹H NMR (300 mHz, CD₃OD): 8.00-8.02 (s, 1H),7.65-7.80 (m, 2H), 7.40-7.50 (t, 1H), 4.60-4.62 (m, 1H), 3.95-4.20 (m,3H) 3.65-3.79 (m, 2H), 3.40-3.60 (m, 2H), 3.10-3.20 (m, 2H), 2.05-2.19(m, 2H), 1.40-1.85 (m, 6H), 1.20-1.30 (m, 4H).

Example 204: Synthesis of3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxypropionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzoicacid a. Preparation of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-benzoic acidmethyl ester

3-endo-(8-Azabicyclo[3.2.1]oct-3-yl)-benzamide (2.5 g, 9.36 mmol) wasweighed into a 200 mL flask and purged with nitrogen. Methanol (100 mL)was added followed by hydrochloride acid in dioxane (7 mL of 4.0 Nsolution, 28 mmol). The solution was heated to reflux and stirredovernight. The methanol was removed via evaporation and the reactionmixture was diluted with DCM (200 mL) and 1N NaOH (150 mL). The aqueouslayer was extracted with DCM (2×50 mL) and combined organic layers werewashed with brine and dried over sodium sulfate. Solvent was removed andthe crude residue was purified by preparative HPLC. Pure fractions werecombined to give the title intermediate (1.66 g) as a white powder.(m/z): [M+H]⁺ calcd for C₁₅H₂₀NO₂, 246; found 246.3.

b. Preparation of3-endo-{8-[2-(benzyloxycarbonyl-cyclohexylmethylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}benzoicacid methyl ester

To a solution of the product of the previous step (1.66 g, 4.61 mmol) inDCM (20 mL) and methanol (20 mL) was addedcyclohexylmethyl-(2-oxoethyl)-carbamic acid benzyl ester (1.27 g, 4.61mmol). The reaction mixture was stirred for 20 min, then sodiumtriacetoxyborohydride (1.95 g, 9.22 mmol) was added. The reactionmixture was stirred for 2 h, and then diluted with DCM (100 mL), washedwith saturated aqueous sodium bicarbonate and brine, and dried oversodium sulfate. Solvent was removed in vacuo to give the titleintermediate (2.65 g, >100% yield) as a crunchy yellow solid which wasused directly in the next step.

c. Preparation of3-endo-{8-[2-(cyclohexylmethylamino)ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl}benzoicacid methyl ester

To a solution of the product of the previous step (2.65 g) in ethanol(20 mL) and 1N aqueous HCl (10 mL) was added palladium on carbon (10 wt.%, 270 mg). The reaction was purged with hydrogen gas and stirred underhydrogen overnight. The catalyst was removed via filtration and thereaction was diluted with DCM (200 mL) and 1N NaOH (150 mL). The aqueouslayer was extracted with DCM (2×50 mL) and combined organic layers werewashed with brine and dried over sodium sulfate. Solvent was removed togive the title intermediate (2.0 g) as a waxy yellow oil. (m/z): [M+H]⁺calcd for C₂₄H₃₆N₂O₂, 385.3; found 385.5.

d. Preparation of3-endo-(8-{2-[cyclohexylmethyl-((S)-2,2-dimethyl-[1,3]dioxolane-4-carbonyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzoicacid methyl ester

To a solution of the product of the previous step (2.0 g, 5.2 mmol) inDMF (35 mL) was added lithium(S)-2,2-dimethyl-[1,3]dioxolane-4-carboxylate (0.72 g, 5.7 mmol,) andHATU (2.18 g, 5.7 mmol). The reaction mixture was stirred at roomtemperature overnight, and then diluted with DCM (100 mL), washed withwater, 1:1 water:saturated aqueous sodium bicarbonate, and brine, thendried over potassium carbonate. Solvent was removed in vacuo to givecrude title intermediate as a brown oil that was used directly in thenext step.

e. Preparation of3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxypropionyl)amino]-ethyl}8-aza-bicyclo[3.2.1]oct-3-yl)benzoicacid methyl ester

The product of the previous step was dissolved in acetonitrile (15 mL)and 1N HCl (15 mL) and the solution was stirred at room temperature for2 h. The reaction mixture was diluted with DCM (200 mL) and 1N NaOH (150mL). The aqueous layer was extracted with DCM (2×50 mL) and combinedorganic layers were washed with brine and dried over sodium sulfate.Solvent was removed in vacuo to give the title intermediate (2.2 g) as ayellow oil. (m/z): [M+H]⁺ calcd for C₂₇H₄₀N₂O₅, 473.3; found 473.3.

f. Synthesis of3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxypropionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzoicacid

To a solution of the product of the previous step (2.2 g, 5.2 mmol) inTHF (5 mL) was added a solution of lithium hydroxide (1.31 g, 31.2 mmol)in water (5 mL). The solution was stirred vigorously at roomtemperature. When the ester hydrolysis was complete, the THF was removedin vacuo and the residue was purified by preparative HPLC. Purefractions were combined to give the title compound (0.32 g) as a whitepowder. (m/z): [M+H]⁺ calcd for C₂₆H₃₈N₂O₅, 459.28; found 459.5.

Assay 1: Radioligand Binding Assay on Human Mu, Human Delta and GuineaPig Kappa Opioid Receptors a. Membrane Preparation

CHO-K1 (Chinese Hamster Ovary) cells stably transfected with human muopioid or with guinea pig kappa receptor cDNA were grown in mediumconsisting of Ham's-F12 media supplemented with 10% FBS, 100 units/mlpenicillin-100 μg/mL streptomycin and 800 μg/mL Geneticin in a 5% CO₂,humidified incubator @ 37° C. Receptor expression levels (B_(max) ˜2.0and ˜0.414 pmol/mg protein, respectively) were determined using[³H]-Diprenorphine (specific activity ˜50-55 Ci/mmol) in a membraneradioligand binding assay.

Cells were grown to 80-95% confluency (<25 subculture passages). Forcell line passaging, the cell monolayer was incubated for 5 minutes atroom temperature and harvested by mechanical agitation in 10 mL of PBSsupplemented with 5 mM EDTA. Following resuspension, cells weretransferred to 40 mL fresh growth media for centrifugation for 5 minutesat 1000 rpm and resuspended in fresh growth medium at the appropriatesplit ratio.

For membrane preparation, cells were harvested by gentle mechanicalagitation with 5 mM EDTA in PBS followed by centrifugation (2500 g for 5minutes). The pellets were resuspended in Assay Buffer (50 mM4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acidN-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) (HEPES)), pH7.4, and homogenized with a polytron disrupter on ice. The resultanthomogenates were centrifuged (1200 g for 5 minutes), the pelletsdiscarded and the supernatant centrifuged (40,000 g for 20 minutes). Thepellets were washed once by resuspension in Assay Buffer, followed by anadditional centrifugation (40,000 g for 20 minutes). The final pelletswere resuspended in Assay Buffer (equivalent 1 T-225 flask/1 mL assaybuffer). Protein concentration was determined using a Bio-Rad BradfordProtein Assay kit and membranes were stored in frozen aliquots at −80°C., until required.

Human delta opioid receptor (hDOP) membranes were purchased from PerkinElmer. The reported K_(d) and B_(max) for these membranes determined bysaturation analyses in a [³H]-Natrindole radioligand binding assays were0.14 nM (pK_(d)=9.85) and 2.2 pmol/mg protein, respectively. Proteinconcentration was determined using a Bio-Rad Bradford Protein Assay kit.Membranes were stored in frozen aliquots at −80° C., until required.

b. Radioligand Binding Assays

Radioligand binding assays were performed in an Axygen 1.1 mL deep well96-well polypropylene assay plate in a total assay volume of 200 μLcontaining the appropriate amount of membrane protein (˜3, ˜2 and ˜20 μgfor mu, delta and kappa, respectively) in Assay Buffer, supplementedwith 0.025% bovine serum albumin (BSA). Saturation binding studies fordetermination of K_(d) values of the radioligand were performed using[³H]-Diprenorphine at 8-12 different concentrations ranging from 0.001nM-5 nM. Displacement assays for determination of pKi values ofcompounds were performed with [³H]-Diprenorphine at 0.5, 1.2, and 0.7 nMfor mu, delta, and kappa, respectively, and eleven concentrations ofcompound ranging from 10 pM-100 μM.

Binding data were analyzed by nonlinear regression analysis with theGraphPad Prism Software package (GraphPad Software, Inc., San Diego,Calif.) using the 3-parameter model for one-site competition. The curveminimum was fixed to the value for nonspecific binding, as determined inthe presence of 10 μM naloxone. K_(i) values for test compounds werecalculated, in Prism, from the best fit IC₅₀ values, and the K_(d) valueof the radioligand, using the Cheng-Prusoff equation(K_(i)=IC₅₀/(1+([L]/K_(d))) where [L]=the concentration of[³H]-Diprenorphine. Results are expressed as the negative decadiclogarithm of the K_(i) values, pK_(i).

Test compounds having a higher pK_(i) value in these assays have ahigher binding affinity for the mu, delta, or kappa opioid receptor. Thecompounds of Examples 1-204 were tested in these assays. With theexception of the compound of Example 204, which demonstrated binding atthe mu receptor at the micromolar level, all of the compounds had apK_(i) value between about 8.0 to about 10.5 at the human mu opioidreceptor. For example, the compounds of Examples 1, 46B, 58, 59, and136, had pK_(i) values of 10.1, 10.0, 9.9, 9.2, and 9.8, respectively.The compounds of Examples 1-203 also had pK_(i) values between about 7.0and about 10.5 at the human delta and guinea pig kappa opioid receptors.

Assay 2: Agonist Mediated Activation of the Mu-Opioid Receptor inMembranes Prepared from CHO-K1 Cells Expressing the Human Mu-OpioidReceptor

In this assay, the potency and intrinsic activity values of testcompounds were determined by measuring the amount of bound GTP-Eupresent following receptor activation in membranes prepared from CHO-K1cells expressing the human mu opioid receptor.

a. Mu Opioid Receptor Membrane Preparation

Human mu opioid receptor (hMOP) membranes were either prepared asdescribed above or were purchased from Perkin Elmer. The reported pK_(d)and B_(max) for the purchased membranes determined by saturationanalyses in a [³H]-Diprenorphine radioligand binding assays was 10.06and 2.4 pmol/mg protein, respectively. Protein concentration wasdetermined using a Bio-Rad Bradford Protein Assay kit. Membranes werestored in frozen aliquots at −80° C., until required. Lyophilized GTP-Euand GDP were diluted to 10 μM and 2 mM, respectively, in doubledistilled H₂O then mixed and permitted to sit at room temperature for 30minutes prior to transfer to individual aliquots samples for storage at−20° C.

b. Human Mu GTP-Eu Nucleotide Exchange Assay

GTP-Eu nucleotide exchange assays were performed using the DELPHIAGTP-binding kit (Perkin/Elmer) in AcroWell 96 well filter platesaccording to the manufacturer's specifications. Membranes were preparedas described above, and prior to the start of the assay, aliquots werediluted to a concentration of 200 μg/mL in Assay Buffer (50 mM HEPES, pH7.4 at 25° C.), then homogenized for 10 seconds using a Polytronhomogenizer. Test compounds were received as 10 mM stock solutions inDMSO, diluted to 400 μM into Assay Buffer containing 0.1% BSA, andserial (1:5) dilutions then made to generate ten concentrations ofcompound ranging from 40 pM-80 μM-GDP and GTP-Eu were diluted to 4 μMand 40 nM, respectively, in Assay Buffer. The assay was performed in atotal volume of 100 μL containing 5 μg of membrane protein, testcompound ranging from 10 pM-20 μM), 1 μM GDP, and 10 nM GTP-Eu dilutedin 10 mM MgCl₂, 50 mM NaCl, and 0.0125% BSA, (final assayconcentrations). A DAMGO (Tyr-D-Ala-Gly-(methyl)Phe-Gly-ol)concentration-response curve (ranging from 12.8 pM-1 μM) was included onevery plate.

Assay plates were prepared immediately prior to assay following theaddition of 25 μL of Assay Buffer, 25 μL of test compound, and 25 μL GDPand GTP-Eu. The assay was initiated by the addition of 25 μL membraneprotein and allowed to incubate for 30 minutes. The assay plates werethen filtered with a Waters vacuum manifold connected to the housevacuum regulated to 10-12 in. Hg and washed with room temperature GTPWash Solution (2×300 mL). The bottoms of the plates were blotted toremove excess liquid. The plates were then immediately read to determinethe amount of bound GTP-Eu by measuring Time Resolved Fluorescence (TRF)on a Packard Fusion Plate ReaderVehicle: DMSO not to exceed 1% finalassay concentration.

The amount of bound GTP-Eu is proportional to the degree of activationof the mu opioid receptors by the test compound. The intrinsic activity(IA), expressed as a percentage, was determined as the ratio of theamount of bound GTP-Eu observed for activation by the test compound tothe amount observed for activation by DAMGO which is presumed to be afull agonist (IA=100). The compounds of Examples 1 to 204 demonstratedintrinsic activities in this assay of less than about 40, typically lessthan about 25. For example, the compounds of Examples 1, 46B, 58, 59,and 136, had IA values of 6, −3, −3, −2, and 14, respectively. Thus, thecompounds of the present invention have been shown to act as antagonistsat the human mu opioid receptor.

Assay 3: Mouse Model of In Vivo Efficacy

In these assays the efficacy of test compounds was evaluated in a modelof gastrointestinal transit, which evaluates peripheral activity, aswell as in an analgesia detection model utilizing a rodent hot plate,which evaluates central nervous system activity. Obtaining results fromthese two models enables calculation of relative peripheralselectivities of test compounds. These studies were approved by theInstitutional Animal Care and Use Committee at Theravance, Inc. andconformed to the Guide for the Care and Use of Laboratory Animalspublished by the National Academy of Sciences (©1996).

a. Mouse Intestinal Transit Assay

Test compounds were evaluated in the mouse intestinal transit assay todetermine their ability to reverse morphine-induced delayedgastrointestinal transit. Mice were fasted up to 24 hours prior toadministration of test compounds or vehicle by intravenous,subcutaneous, intramuscular or oral routes of administration at dosesranging from 0.001 to about 10 milligrams/kilogram (mg/kg). Theadministration of test compound was followed by subcutaneousadministration of morphine at a dose of 3 mg/kg or vehicle. Five minutespost morphine or vehicle administration, a non-nutritive, non-absorbablecharcoal meal was administered via oral gavage and animals were allowedfree access to water for the sixty minute duration of the experiment.Animals were then euthanized via carbon dioxide asphyxiation followed bythoracotomy and the stomach to caecum was carefully excised. The stomachwas ligated at the lower esophageal sphincter and the pyloric sphincterto prevent additional emptying into the small intestine during theperiod in which measurements were made. Intestinal transit was definedas the distance traveled by the leading front of the meal relative tothe total intestinal length (at the ileocecal junction).

b. Mouse Hot Plate Assay

Activities of compounds were investigated in the mouse hot plate model(Letica Scientific Instruments Model #7406; Panlab, S. L., Barcelona,Spain) to determine their ability to reverse the centrally mediatedaction of morphine. Compounds were evaluated as to their ability toreverse morphine-induced analgesia as evidenced by decreases in paw licklatency relative to morphine controls. Test compounds were administeredintravenously, subcutaneously, intramuscularly or orally at dosesranging from 0.1 to 30 mg/kg followed by subcutaneous administration ofmorphine at a dose of 10 mg/kg or of vehicle. Animals were then returnedto their home cage for the thirty minute remainder of the experiment.Animals were subsequently placed on the hot plate apparatus (53° C.) andthe time for the mouse to lick its paw was recorded by an observerblinded to the treatment group. Animals that failed to present paw lickbehavior prior to a 35 second cut-off were automatically assigned alatency time of 35 seconds.

c. Data Analysis and Results

Data was analyzed using the GraphPad Prism Software package (GraphPadSoftware, Inc., San Diego, Calif.). Percent reversal curves wereconstructed by non-linear regression analysis using the sigmoidal doseresponse (variable slope) model and best-fit ID₅₀ values werecalculated. Curve minima and maxima were fixed to morphine controlvalues (indicating 0% reversal) and vehicle controls (indicating 100%reversal), respectively. Results are expressed as ID₅₀, the doserequired for 50% reversal of the effects of morphine, in milligrams perkilogram. Selected compounds of the invention were tested in this model.Compounds of the invention administered subcutaneously or orallyexhibited ID₅₀ values in the intestinal transit model of between about0.1 and about 3 mg/kg.

Peripheral selectivity was calculated for each compound based on thehotplate ID₅₀ value (central measure) divided by the intestinal transitID₅₀ value (peripheral measure). The compounds of the invention, whichwere tested in these assays, exhibited peripheral selectivities rangingfrom about 2 fold to about 500 fold. In particular, the compounds ofExamples 46B, 48B, 58, 59, and 63 exhibited peripheral selectivities of15, 30, 300, 43, and 22, respectively, following subcutaneousadministration, and 19, 42, 35, 6, and 22, respectively, following oraladministration.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto. Additionally, all publications, patents, andpatent documents cited hereinabove are incorporated by reference hereinin full, as though individually incorporated by reference.

What is claimed is:
 1. A process for preparing a product compound of theformula

or a pharmaceutically acceptable salt thereof, the process comprising:(a) reacting a compound of the formula

with a compound of the formula:

or an alkyli metal salt thereof to provide a protected intermediate ofthe formula:

and (b) deprotecting the protected intermediate to provide the productcompound or a pharmaceutically acceptable salt thereof.
 2. The processof claim 1 wherein the alkali metal salt is a lithium salt.